European Heart Journal (2021) 42, 2235–2259 STATE OF THE ART REVIEW doi:10.1093/eurheartj/ehab128 Thrombosis and antithrombotic treatment Antithrombotic therapy in diabetes: which, when, and for how long? Ramzi A. Ajjan 1*, Noppadol Kietsiriroje 1,2, Lina Badimon 3,4,5 , Gemma Vilahur3,4, Diana A. Gorog 6,7, Dominick J. Angiolillo8, David A. Russell 1,9, Bianca Rocca 10, and Robert F. Storey11 1 The LIGHT Laboratories, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 7JT, UK; 2Endocrinology and Metabolism Unit, Internal Medicine Department, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand; 3Cardiovascular Program ICCC, Research Institute Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Sant Antoni M. Claret 167, 08025 Barcelona, Spain; 4Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Sant Antoni M. Claret 167, 08025 Barcelona, Spain; 5Cardiovascular Research Chair, Universidad Autónoma Barcelona (UAB), Sant Antoni M. Claret 167, 08025 Barcelona, Spain; 6University of Hertfordshire, College Lane Campus Hatfield, Hertfordshire AL10 9AB, UK; 7National Heart and Lung Institute, Guy Scadding Building, Dovehouse St, London SW3 6LY, UK; 8Division of Cardiology, University of Florida College of Medicine – Jacksonville, 655 West, 8th Street, Jacksonville, FL 32209, USA; 9Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK; 10Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy; and 11Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK Received 6 December 2020; revised 26 January 2021; editorial decision 13 February 2021; accepted 23 February 2021; online publish-ahead-of-print 25 March 2021 Cardiovascular disease remains the main cause of mortality in individuals with diabetes mellitus (DM) and also results in significant morbid- ity. Premature and more aggressive atherosclerotic disease, coupled with an enhanced thrombotic environment, contributes to the high vascular risk in individuals with DM. This prothrombotic milieu is due to increased platelet activity together with impaired fibrinolysis sec- ondary to quantitative and qualitative changes in coagulation factors. However, management strategies to reduce thrombosis risk remain largely similar in individuals with and without DM. The current review covers the latest in the field of antithrombotic management in DM. The role of primary vascular prevention is discussed together with options for secondary prevention following an ischaemic event in dif- ferent clinical scenarios including coronary, cerebrovascular, and peripheral artery diseases. Antiplatelet therapy combinations as well as combination of antiplatelet and anticoagulant agents are examined in both the acute phase and long term, including management of individ- uals with sinus rhythm and those with atrial fibrillation. The difficulties in tailoring therapy according to the variable atherothrombotic risk in different individuals are emphasized, in addition to the varying risk within an individual secondary to DM duration, presence of complications and predisposition to bleeding events. This re- view provides the reader with an up-to-date guide for antithrombotic management of individuals with DM and highlights gaps in know- ledge that represent areas for future research, aiming to improve clinical outcome in this high-risk population. ................................................................................................................................................................................................... * Corresponding author. Tel: þ44 113 2064 963, Email: r.ajjan@leeds.ac.uk C The Author(s) 2021. Published on behalf of the European Society of Cardiology. All rights reserved. V This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestrict- ed reuse, distribution, and reproduction in any medium, provided the original work is properly cited. For permissions, please email: journals.permissions@oup.com. 2236 R.A. Ajjan et al. Graphical Abstract Altered acvity of coagulaon factors Primary prevenon Compact clots Single anplatelet therapy Hypofibrinolysis Secondary prevenon Increased platelet reacvity Anplatelet monotherapy Dual anplatelet therapy Anplatelet & ancoagulant Prothromboc environment Coronary Cerebrovascular Peripheral artery artery Atherothrombosis in diabetes. ................................................................................................................................................................................................... Keywords Diabetes • Cardiovascular • Cerebrovascular • Peripheral artery disease • Antithrombotic • Antiplatelet .. Introduction .. .. risks of antithrombotic therapy combinations, with the overall aim of providing the reader with an up-to-date guide for antithrombotic Despite advances in therapy, a diagnosis of diabetes mellitus (DM) is .. management in DM. Search strategy is detailed in the Supplementary .. associated with increased morbidity and reduced lifespan, mainly due .. material online, S1. to vascular complications.1–3 Premature and more severe vascular .. .. disease, as well as a prothrombotic environment, represent key .. mechanisms for adverse vascular outcomes in this population.4 The .. The thrombotic environment in .. prothrombotic milieu develops secondary to increased platelet re- .. .. diabetes activity coupled with hypofibrinolysis.5,6 .. Current treatment strategies to improve vascular outcomes in .. Individuals with DM are prone to both arterial and venous throm- .. individuals with DM are focused on revascularization of acute athero- .. bosis.7 DM is characterized by multiple pathological processes, thrombotic occlusions, where possible, together with early introduc- .. including hyperglycaemia, chronic inflammation, oxidative stress, and .. tion of antithrombotic therapies, usually by inhibiting platelet .. associated metabolic conditions, that damage the endothelium and function. This continues long-term coupled with multifactorial ther- .. increase platelet reactivity, resulting in a prothrombotic environment. .. apy targeting hypertension, dyslipidaemia and dysglycaemia in order .. Endothelial dysfunction is a consistent finding in DM patients and con- to limit the progression of vascular pathology. .. tributes to the prothrombotic shift (Figure 1).4 .. In this review, we discuss the latest in antithrombotic therapies for .. An array of mechanisms operate in platelets to enhance their re- the management of coronary artery disease (CAD), cerebrovascular .. activity.8 Hyperglycaemia is associated with higher expression of .. disease, and peripheral artery disease (PAD) in DM, covering thera- .. platelet receptors, including glycoprotein (GP) Iba, GPIIb/IIIa and pies for primary prevention, acute vascular occlusion and long-term .. P2Y12,9 reduced platelet membrane fluidity secondary to increased .. secondary prevention. Special emphasis is placed on the benefits and . glycation, higher thromboxane (TX) A2 synthesis together with Antithrombotic therapy in diabetes 2237 Figure 1 Diabetes enhances the risk of thrombosis. Diabetes induces endothelial dysfunction with subsequent decline in the expression/release of molecules that can reduce platelet activation and associated thrombus formation. At a platelet level, there are several mechanisms by which diabetes could enhance platelet susceptibility to activation including: (i) a higher abundance of advanced glycation end-products (AGEs) which induces insulin resistance and alters membrane fluidity; (ii) an enhanced oxidative stress which leads to the formation of isoprostanes which in turn induce platelet activation by interacting with the thromboxane receptor (TP); (iii) a higher production of thromboxane (TXA2); and (iv) an increased expression of multiple platelet activation receptors and a higher reactivity to several platelet agonists. As for coagulation, diabetes is associated with a higher amount of tissue factor (TF), thrombin (factor II), and fibrinogen production, which, in concurrence with lower anticoagulant proteins [protein C- antithrombin III complex (PC/ATIII)], favours the formation of the fibrin mesh, which undergoes glycation and oxidative modifications, becoming more dense and resistant to fibrinolysis. Diabetes is also associated with a hypofibrinolytic state characterized by higher abundance of inhibitors of tis- sue plasminogen activator (tPA) such as plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI), and increased incorporation of antifibrinolytic proteins into the clot [plasmin inhibitor (PI) and complement 3 (C3)] which collectively reduce the efficiency of fibrin- olysis. AA: arachidonic acid; ADP: adenosine diphosphate; Cox: cyclooxygenase; GP: glycoprotein; IRc: insulin receptors; miR: microRNAs; NO: nitric oxide; PAR: protease-activated receptor; PGI2: prostacyclin; ROS: reactive oxygen species; TM: thrombomodulin; VLDL: very-low-density lipopro- tein; vWF: von Willebrand factor. increased platelet activation markers.10–12 Diabetes-associated oxi- .. interleukin (IL)-1 and IL-6, selectin, soluble CD40 ligand],17,25 besides .. dative stress also increases production of F2-isoprostanes.13 TXA2 .. enhancing platelet reactivity, favour a hypercoagulable environment. .. and F2-isoprostanes, in turn, activate the thromboxane receptors .. Furthermore, bone marrow transplants that created chimeras of nor- and amplify platelet activation (Figure 1).14 Platelet hyper-reactivity .. mal rats with bone marrow cells from diabetic rats resulted in a pro- .. also results from diminished sensitivity to the inhibitory agents pros- .. thrombotic phenotype similar to the donor animals, indicating the tacyclin, nitric oxide, and insulin,15–17 and from changes in platelet .. imprinting effects of DM on haematopoietic cells.22 .. content of miRNAs known to regulate platelet function (miR-223, .. Several prothrombotic alterations in the coagulation-fibrinolytic miR-26b, miR-126, miR-140).18,19 Moreover, the imbalance in intra- .. system also occur in DM,26 including increased levels of tissue factor, .. platelet magnesium and calcium homeostasis renders platelets more .. prothrombin, factor VII and fibrinogen coupled with impaired anti- sensitive to epinephrine, adenosine diphosphate (ADP), and throm- .. coagulant and fibrinolytic activity (Figure 1).27 Diabetic thrombi dis- .. bin.20 DM is also characterized by accelerated platelet turnover, as .. play compact fibrin networks with densely-packed thin fibres that are evidenced by release of more reactive, reticulated platelets21,22 that .. resistant to fibrinolysis.6,26 Furthermore, hyperglycaemia induces .. display a reduced response to antiplatelet agents.23 Finally, platelets .. qualitative changes in plasminogen, hindering its fibrinolytic activity.28 from DM patients more easily externalize phosphatidylserine in the .. Concomitantly, elevated levels of anti-fibrinolytic proteins (plasmino- .. outer platelet membrane, thereby providing a better surface for the .. gen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibi- assembly of clotting factors and tissue factor activation.21,22 .. tor),29 along with increased incorporation of anti-fibrinolytic proteins .. Other associated metabolic conditions like obesity, dyslipidaemia, .. (complement C3 and plasmin inhibitor) into the clot further com- and systemic inflammation also contribute to thrombosis risk.6,24 .. promise fibrinolysis.6 Despite this prothrombotic environment, DM .. Circulating inflammatory molecules [tumour necrosis factor-a, .. patients have a paradoxical increased risk of bleeding, particularly 2238 R.A. Ajjan et al. .. following an acute coronary syndrome (ACS).30 However, data on .. Antiplatelet therapy for primary stable patients are less clear: the dual antiplatelet therapy (DAPT) .. .. prevention of ischaemic events study (detailed below under ‘Secondary Prevention’) reported no in- .. crease in long-term moderate or severe bleeding events in those .. .. Primary prevention is defined as offering therapy to individuals with- with DM, possibly related to excluding those with bleeding events in .. out a history of a vascular ischaemic event. In the largest individual the first 12 months, while increased risk was documented in the .. .. data meta-analysis of primary prevention trials (n = 95 000 individu- REACH and CORONOR registries.31,32 The exact mechanisms for .. als), aspirin use in DM was associated with a non-significant 12% rela- the increase in both thrombosis and bleeding risk in some diabetes .. .. tive risk reduction (RRR) of major adverse cardiac events (MACE), patients are not fully understood, although renal complications may .. from 1.87% to 1.63% per year [hazard ratio (HR) 0.88 (0.67–1.15); have a role.33 Also, chronic activation of platelet and coagulation pro- .. .. Table 1].42 Although non-significant, this benefit was comparable to teins may ‘exhaust’ the system in some DM patients, thus increasing .. non-DM individuals, in whom aspirin reduced yearly MACE from bleeding risk.34 .. .. 0.57% to 0.51% [HR 0.88 (0.82–0.94); P = 0.0001].42 Aspirin was .. associated with an increase in extracranial, mainly gastrointestinal, .. .. bleeding in both non-DM and DM populations (P = 0.20 for hetero- .. geneity; Table 1).42 Following this meta-analysis, the Japanese Primary .. Antithrombotic targets .. Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) .. (n = 2539)43 and prevention of progression of arterial disease and dia- For decades, the two main antithrombotic targets have been platelet .. .. betes (POPADAD) (n = 1276)44 trials investigated aspirin in primary TXA2 production and platelet P2Y12 receptor activation. .. prevention but, being small and underpowered, failed to provide con- .. .. clusive data. The recent ASCEND trial is the largest, longest and only .. Aspirin .. adequately powered trial investigating primary prevention in DM, .. randomizing 15 480 DM patients without symptomatic cardiovascu- Low-dose aspirin irreversibly inhibits platelet cyclooxygenase-1 en- .. .. lar disease to aspirin (100 mg daily) or placebo.45 Serious vascular zyme, preventing the conversion of arachidonic acid into bioactive .. events occurred in 8.5% of individuals on aspirin vs. 9.6% on placebo prostanoid TXA2.35 Given the short half-life of aspirin and increased .. .. [RRR 12%, HR 0.88 (0.79–0.97); P = 0.01]. Major bleeding, according platelet turnover in DM, a proportion of platelets may escape 24-h .. to the Bleeding Academic Research Consortium (BARC) 2, 3, and 5 inhibition by once-daily aspirin, which can be re-established by twice- .. .. categories,46 occurred in 4.1% and 3.2% in the aspirin and placebo daily dosing.23,36 .. arms, respectively, without significant differences in fatal or intracra- .. .. nial bleeding, although the absolute number of events was low .. (Table 1).45 Notably, >50% of major bleeding excess with aspirin was P2Y12 receptor antagonists .. .. gastrointestinal. The number needed to treat (NNT)/number needed ADP-stimulated effects on platelets are mediated primarily by Gi- .. to harm (NNH) ratio was 0.8, favouring treatment. Importantly, .. coupled P2Y12 receptor activation, leading to persistent platelet ag- .. BARC 2–5 bleeding criteria are less restrictive as compared to the gregation, whereas P2Y1 is responsible for an initial weak, transient .. Thrombolysis in Myocardial Infarction (TIMI) major criteria.47–49 Of .. phase of platelet aggregation.37 There are two main classes of orally .. note, there was no significant heterogeneity in the effect of aspirin administered P2Y12 inhibitors: thienopyridines (ticlopidine, clopidog- .. according to the estimated vascular risk at baseline. A meta-analysis .. rel, and prasugrel) and non-thienopyridine agents (ticagrelor).38 .. of 12 randomized controlled trials (RCTs) (34 227 individuals), Thienopyridines require conversion to an active metabolite that acts .. including the ASCEND population, showed that aspirin reduces .. irreversibly. Ticlopidine is no longer marketed in many countries due .. MACE by 11% compared with placebo [HR 0.89 (0.83–0.95)] to safety concerns.38 Ticagrelor is a direct-acting cyclopentyltriazolo- .. (Table 1).50 .. pyrimidine that requires no metabolism and binds reversibly to the .. The THEMIS study tested intensification of antiplatelet regimen in P2Y12 receptor.38 .. .. 19 220 DM patients without previous myocardial infarction (MI) or .. stroke but with evidence of clinical CAD and already on low-dose as- .. .. pirin therapy (Table 1).47 Individuals randomized to aspirin and tica- Other antithrombotic approaches .. grelor had a modest reduction in vascular events compared with .. Warfarin and other vitamin K antagonists (VKAs) require regu- .. aspirin alone [7.7% and 8.5%, respectively, HR 0.90 (0.81–0.99); lar monitoring and this, together with high bleeding risk when .. P = 0.04], associated with a 2.3-fold increase in TIMI major bleeding .. combined with antiplatelet therapy, prevented widespread .. and a 1.7-fold increase in intracranial bleeding (Table 1), giving an un- use. 39 More modern approaches include modulation of throm- .. favourable NNT/NNH ratio of 1.48 and arguing against routine .. bin activity either by blocking protease-activated receptor-1 on .. DAPT with aspirin and ticagrelor in this population. platelet membrane (vorapaxar)40 or by directly inhibiting pro- .. The recent European Society of Cardiology (ESC) guidelines indi- .. tein function (dabigatran). 41 Other non-VKA oral anticoagu- .. cate that those with DM and >_1 organ damage or >_3 major risk fac- lants (NOAC) include inhibitors of activated factor Xa .. tors, or any risk factor and >_10 years disease duration without organ .. (apixaban, rivaroxaban, and edoxaban).41 Supplementary ma- .. damage, should be considered for primary prevention, in the absence terial online, Table S1 provides a summary of the main antith- .. of contraindications (Supplementary material online, Table S2) but .. rombotic agents. . routine use of aspirin for all DM individuals is not recommended.51 Table 1 Primary prevention in diabetes Study Patients Primary efficacy Median Predicted vs. Absolute and Absolute and Comments endpoint follow-up observed incidence relative benefit relative harm and expected benefit ................................................................................................................................................................................................................................................................................................ ATT meta-analysis 95 000 patients from six Stroke, MI, and CV death NA NA Overall population: GI/extracranial bleed NNT/NNH ratio: 0.83 (2009)42 primary prevention tri- Aspirin: 0.51% Overall population: No difference in fatal Antithrombotic therapy in diabetes als which included 4% Control: 0.57% Aspirin: 0.10% bleeding of DM patients HR 0.88 (0.82–0.94) Control: 0.07% (n = 3818) DM subgroup: HR 1.54 (1.30–1.82) Aspirin: 1.63% DM subgroup: Control: 1.87% Aspirin: 0.23%/year HR 0.88 (0.67–1.15) Control: 0.21%/year HR 1.10 (0.52–2.34) JPAD (2008)43 2539 T2DM patients Sudden death; death from 4.4 years Predicted: 5.2%/year Aspirin: 5.4% Any GI bleeding: Observed primary end- without a history of coronary, cerebrovas- vs. Placebo: 6.7% Aspirin: n = 12 point rate 1/3 of atherosclerotic disease cular, and aortic causes; Observed: 1.7%/year HR 0.80 (0.58–1.10) Placebo: n = 4 predicted. non-fatal acute MI; UA; Expected benefit: Expected benefit likely exertional angina; non- 30% RRR unrealistic based on fatal ischaemic and previous data (trial haemorrhagic stroke; largely TIA; or non-fatal aortic underpowered). and PVD POPADAD (2008)44 1276 adults aged Death from CAD or 6.7 years Predicted: 28%/year Aspirin: 18.2% Any GI bleeding: Observed events were >_40 years with T1DM stroke, non-fatal MI or vs. Placebo: 18.3% Aspirin: 4.4% approx. 1/10 of or T2DM and ABI stroke, or amputation observed: 2.9%/year HR 0.98 (0.76–1.26) Placebo: 4.9% predicted. <_0.99 (asymptomatic) for critical limb ischae- Expected benefit: HR 0.90 (0.53–1.52) The expected benefit was mia; and death from 25% RRR likely unrealistic based CAD or stroke on previous data (trial was largely underpowered). ASCEND (2018)45 15 480 Patients aged >_40 Non-fatal MI, non-fatal 7.4 years Predicted: 1.2–1.3%/year Aspirin: 8.5% BARC 2, 3, and 5 bleeding: Consistency between years with DM and no stroke (excluding con- vs. Placebo: 9.6% Aspirin: 4.1% predicted and evident CV disease firmed ICH), TIA, or Observed: 1.3%/year HR 0.88 (0.79–0.97) Placebo 3.2% observed incidence death from any vascular Expected benefit: HR 1.29 (1.09–1.52) event rate Continued 2239 2240 Table 1 Continued Study Patients Primary efficacy Median Predicted vs. Absolute and Absolute and Comments endpoint follow-up observed incidence relative benefit relative harm and expected benefit ................................................................................................................................................................................................................................................................................................ cause (excluding con- 15% RRR ICH: NNT/NNH: 0.81 firmed ICH) Aspirin: 0.7% Placebo: 0.6% HR 1.22 (0.82–1.81) Fatal bleeding: Aspirin: 0.2% Placebo: 0.2% HR 1.18 (0.61–2.30) THEMIS (2019)47 19 220 patients with DM, Stroke, MI, and CV death 3.3 years Predicted benefit: 16% Ticagrelor: 7.7% TIMI major bleeding: High rate of ticagrelor >_50 years, stable CAD RRR Placebo: 8.5% Ticagrelor: 2.2% discontinuation: with no previous MI or Predicted: 2.5%/year HR 0.90 (0.81–0.99) Placebo: 1.0% Placebo 25% vs. stroke vs. HR 2.32 (1.82–2.94) Ticagrelor: 35% Randomized to ticagrelor Observed: 2.5%/year BARC 3–5 bleeding: HR 1.50 (1.42–1.58) or placebo on a back- Ticagrelor: 3.7% Predicted benefit higher ground of aspirin Placebo: 1.7% than observed. therapy HR 2.36 (1.96–2.84) NNT/NNH: 1.48 (TIMI- ICH: major defined Ticagrelor: 0.7% bleeding) Placebo: 0.5% HR 1.71 (1.18–2.48) Meta-analysis 34 227 participants with Stroke, MI, and CV death 5 years NA Aspirin: 8.6% Major bleeding: Seidu et al. (2019)50 DM, individual patient Control: 9.6% Aspirin: 4% data from 2306 HR 0.89 (0.83–0.95) Control: 3.5% participants HR 1.30 (0.92–1.82) Summary of primary prevention studies. Significant differences are reported in bold. ABI, ankle-brachial index; BARC, Bleeding Academic Research Consortium; CAD, coronary artery disease; CV, cardiovascular; DM, diabetes mellitus; GI, gastrointestinal; HR, hazard ratio; ICH, intracranial haemorrhage; MI, myocardial in- farction; NA, not applicable; NNH, number needed to harm; NNT, number needed to treat; PVD, peripheral vascular disease; RRR, relative risk reduction; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TIA, transient is- chaemic attack; TIMI, Thrombolysis in Myocardial Infarction; UA, unstable angina. R.A. Ajjan et al. Antithrombotic therapy in diabetes 2241 .. Overall, guidelines recommend aspirin monotherapy for DM patients .. percutaneous coronary intervention (PCI) for ACS or chronic cor- with additional risk factor(s) and/or with an estimated annual risk of .. onary syndromes (CCS).73 Monotherapy reduced the primary end- .. vascular events >_1% (Supplementary material online, Table S2).52–54 .. point of BARC type 2, 3, or 5 bleeding compared with DAPT at .. 12 months [4.0% vs. 7.1%, HR 0.56 (0.45–0.68); P < 0.001], similarly in .. .. those with and without DM, without increasing the secondary com- Secondary prevention in the .. bined endpoint of death, MI, or stroke. More specifically, ticagrelor .. absence of atrial tachyarrhythmias .. monotherapy in the DM subgroup did not increase ischaemic events .. compared with DAPT [4.6% vs. 5.9%; HR 0.77 (0.55–1.09); P = 0.14] .. Following acute coronary events .. but significantly decreased bleeding complications [4.5% vs. 6.7%; HR .. 0.65 (0.47–0.91); P = 0.012].74 The GLOBAL LEADERS trial random- ACS guidelines recommend DAPT comprising aspirin and prasugrel .. or ticagrelor, which applies to DM individuals.3,51,55,56 Patients with .. ized individuals undergoing PCI with drug-eluting stents for CCS or .. ACS to standard care (DAPT for 12 months followed by aspirin DM, however, exhibit enhanced platelet reactivity and reduced sensi- .. .. alone) or ticagrelor with aspirin for 1 month followed by ticagrelor tivity to thienopyridines (but not ticagrelor),57,58 although the clinical .. .. monotherapy for 23 months. The study failed to show superiority for significance of these biochemical observations remains unclear. .. the intervention, although a trend towards a reduction in the primary .. composite endpoint of death or new Q-wave infarction was apparent .. Aspirin .. [HR 0.87 (0.75–1.01); P = 0.073]. Risk of bleeding was almost identical Guidelines recommend routine early administration of aspirin in .. in the two groups, regardless of DM status.75,76 The more recent ana- .. ACS, which seems to offer similar benefits in individuals with and .. lysis of the subgroup of DM individuals and CKD (higher risk of without DM. Based on pharmacodynamic studies in DM,23,59,60 the .. thrombosis and bleeding) showed no significant reduction in the pri- .. clinical benefit of twice-daily aspirin administration is being evaluated .. mary endpoint with the intervention, although lower rates of the in the ANDAMAN trial (NCT02520921). Higher aspirin doses (300– .. .. patient-oriented composite endpoint (POCE; death, stroke, site- 325 mg vs. 75–100 mg) failed to reduce MACE 30 days post-ACS in .. reported MI/revascularization) were observed in the ticagrelor group the CURRENT-OASIS 7 study (23% had DM).61 The ongoing .. .. compared with controls [20.6% vs. 25.9%, HR 0.74 (0.55–0.99)] with ADAPTABLE study is assessing alternative aspirin dosing, although .. similar reduction in net adverse clinical events (POCE plus BARC 3 this is not limited to the DM population.62 Moreover, ongoing studies .. .. and 5 bleeding events) [22.7% vs. 28.3%, HR 0.75 (0.56–0.99)].77 are aiming to identify new low-dose aspirin formulations with poten- .. Moreover, a recent meta-analysis has shown that, following PCI, tially improved safety and efficacy profiles.63,64 .. .. monotherapy with a P2Y12 inhibitor is preferable to DAPT in older .. individuals and those with diabetes, CKD or multivessel disease due .. P2Y12 inhibitors .. to reduction in bleeding risk.78 Therefore, de-escalation of DAPT In individuals with DM, prasugrel or ticagrelor combination with as- .. may be an option in some patients, particularly when using potent .. pirin is preferred to clopidogrel, which shows reduced effi- .. P2Y12 inhibitors as monotherapy.79 However, de-escalation is per- cacy.30,56,65–67 Post hoc analysis of the DM population in the .. haps best avoided in the DM population, given the high vascular risk, .. TRITON-TIMI 38 trial showed marked benefit of prasugrel over clo- .. unless there are major concerns over bleeding risk and this remains pidogrel,66 while, in PLATO, the absolute benefit of ticagrelor over .. an area for future research. .. clopidogrel was greatest in patients with both DM and chronic kidney .. disease (CKD).68 In patients with ACS and insulin-requiring DM, tica- .. .. Glycoprotein IIb/IIIa inhibitors grelor may achieve more potent platelet inhibition than prasugrel,57 .. although the clinical significance is unclear. The recent ISAR-REACT .. GP inhibitor (GPI) use in ACS significantly reduced 30-day mortality, .. particularly in DM patients undergoing PCI, but this benefit was 5 study, an open-label trial, demonstrated superiority of a prasugrel- .. .. observed before routine P2Y12 inhibitor use.80 Abciximab reduced based strategy over a ticagrelor-based strategy in reducing MACE in .. .. MACE in ACS patients undergoing PCI, even with clopidogrel pre- ACS patients.69 However, this was not the case in the DM subgroup: .. treatment, but the benefit in DM patients was less pronounced the composite primary endpoint (death, stroke, or MI) occurred in .. (abciximab has now been withdrawn in Europe).81 In contemporary 11.2% and 13.0% in ticagrelor and prasugrel arms, respectively [HR .. .. practice using potent P2Y12 inhibitors, GPI therapy is mainly reserved 0.84 (0.58–1.24); P = 0.383] with treatment interaction shown for .. for ‘bail-out’ in case of no-reflow or a thrombotic complication dur- DM status (P = 0.0035).70 Bleeding complications were similar in tica- .. .. ing PCI,82 although some benefit has been suggested also in opiate- grelor- and prasugrel-treated DM individuals. .. treated patients undergoing emergency PCI.83 A difficulty with more potent oral P2Y12 inhibitors is the limited .. .. evidence in the older population who are at higher bleeding risk. .. Two smaller studies in ACS patients aged >_70 years, of whom a third .. Very-low-dose non-VKA oral anticoagulant .. had DM, indicated that de-escalation from prasugrel or ticagrelor to .. In the ATLAS ACS 2-TIMI 51 trial, the addition of very-low-dose clopidogrel may be safe.71 Moreover, platelet-function-guided de-es- .. rivaroxaban (2.5 mg twice daily) to DAPT (in the form of aspirin and .. calation from prasugrel to clopidogrel at hospital discharge may be .. clopidogrel) in ACS patients, of whom 32% had DM, significantly non-inferior to continued prasugrel but this strategy appears safer in .. reduced MACE compared to placebo but the DM group appeared to .. those without DM.72 The TWILIGHT study (n = 7119) assessed .. derive less benefit.84 An increase in bleeding events, including intra- safety of de-escalating DAPT, from ticagrelor plus aspirin to ticagre- .. cranial, was documented and therefore this triple therapy (TT) can .. lor monotherapy, after 3 months of DAPT following high-risk . only be advocated for individuals at very high vascular risk with 2242 R.A. Ajjan et al. Figure 2 Summary of antiplatelet and anticoagulant therapies in individuals with diabetes and vascular disease. ACS: acute coronary syndrome; AF: atrial fibrillation; CAD: coronary artery disease; CVD: cerebrovascular disease; DAPT: dual antiplatelet therapy; NOAC: non-vitamin K antagonist oral anticoagulants; PAD: peripheral artery disease; SR: sinus rhythm. aDiabetes mellitus individuals with >_1 organ damage or >_3 major risk factors, or any risk factor and >_10-year disease duration without organ damage. bActive bleeding or comorbidities with high bleeding risk. cHistory of intra- cerebral haemorrhage or ischaemic stroke, history of other intracranial pathology, recent gastrointestinal bleeding or anaemia due to possible gastro- intestinal blood loss, other gastrointestinal pathology associated with increased bleeding risk, liver failure, bleeding diathesis or coagulopathy, extreme old age or frailty, or renal failure requiring dialysis or with estimated glomerular filtration rate <15 mL/min/1.73 m2. dDiffuse multivessel CAD with at least one of the following: diabetes mellitus requiring medication, recurrent myocardial infarction, PAD, or chronic kidney disease with estimated glomerular filtration rate 15–59 mL/min/1.73 m2. relatively low bleeding risk, accepting the challenge that ischaemic .. Prolonged DAPT significantly reduced the composite of all-cause .. and bleeding risk factors overlap substantially.55 A summary of the .. mortality, MI, or stroke [4.3% vs. 5.9%, HR 0.71 (0.59–0.85); agents used following ACS is given in Figure 2. .. P < 0.001] but at the expense of increased moderate/severe bleeding .. .. events [2.5% vs. 1.6%, HR 1.61 (1.21–2.16); P = 0.001]. However, in .. DM patients (n = 3391), this strategy did not affect the composite .. Long-term therapy for secondary .. outcome [6.6% vs. 7.0%, HR 0.92 (0.71–1.20); P = 0.55] although the prevention .. limitation of subgroup analysis should be acknowledged.89,90 .. Default practice is DAPT for 1 year post-ACS followed by antiplate- .. The PEGASUS-TIMI 54 trial evaluated prolonged ticagrelor use in let monotherapy, usually with aspirin. However, DM patients have .. 21 162 patients with a history of MI 1–3 years prior to enrolment. .. increased long-term risk of recurrent atherothrombotic events and .. Patients also needed to have at least one additional risk factor, which .. should be carefully considered for more intensive long-term antith- .. included DM requiring medication.91 Patients were randomized to ei- rombotic therapy.85 .. ther one of two doses of ticagrelor (90 mg twice daily or 60 mg twice .. The CAPRIE trial (n = 19 185) showed that clopidogrel for second- .. daily) or placebo in addition to aspirin. At 3 years, the primary efficacy ary prevention (75 mg daily) reduced the composite endpoint of is- .. endpoint (cardiovascular death, MI, and stroke) was reduced with .. chaemic stroke, MI, or vascular death compared with daily 325 mg .. ticagrelor 60 mg twice daily compared with placebo [7.8% vs. 9.0% in aspirin [5.32% vs. 5.83% (0.3–16.5); P = 0.043], mostly driven by PAD .. placebo, HR 0.84 (0.74–0.95); P = 0.004]. TIMI major bleeding events .. events, which showed a significant heterogeneity vs. MI and stroke.86 .. increased [2.30% vs. 1.06% in placebo, HR 2.32 (1.68–3.21); DM patients (n = 3866) showed a similar pattern (P = 0.36 for inter- .. P < 0.001], but no difference was detected in fatal or intracranial .. action) but with an amplified absolute risk reduction (15.6% vs. .. bleeding. Similar data were documented in the DM subgroup 17.7%; P = 0.042), without an increase in bleeding events.87 Given the .. (n = 6806, 32% of study population) with a higher absolute risk reduc- .. high aspirin dose used, it is difficult to recommend a routine switch to .. tion in the 60 mg twice daily ticagrelor arm compared with placebo clopidogrel for secondary prevention, except in special clinical scen- .. (11.6% vs. 10.0% in DM subgroup and 7.8% vs. 6.7% in non-DM sub- .. arios, such as individuals with PAD (discussed below). The benefit of .. group). TIMI major bleeding in those with DM was higher in 12 vs. 30 months of DAPT, mostly consisting of aspirin and clopidog- .. ticagrelor-treated individuals compared with placebo [2.5% and 1.0%, .. rel, was tested in the DAPT trial,88 including 9961 individuals who .. HR 2.5 (1.4–4.4); P = 0.0004], an increase that was similar to the non- had not experienced ischaemic or bleeding events at 1 year post-PCI. .. DM group (2.39%; P = 0.89).91 Antithrombotic therapy in diabetes 2243 The COMPASS study in patients with either prior MI or multives- .. cessation (i.e. by the time of hospital discharge).114,115 ESC guid- .. sel CAD (n = 27 395; 38% with DM) showed that rivaroxaban 2.5 mg .. ance endorses TT for at least 1 month if stent thrombosis risk twice daily added to low-dose aspirin reduced the risk of MACE .. outweighs bleeding risk, followed by an antiplatelet agent (usual- .. compared with aspirin alone [4.1% vs. 5.4%, HR 0.76 (0.66–0.86); .. ly clopidogrel) and OAC until 12 months post-PCI, and there- P < 0.001],92 making this an option,85,92,93 particularly in DM patients .. after OAC monotherapy, unless long-term dual therapy is .. who showed greater absolute net benefit.94 While the combination .. considered due to very high ischaemic risk with low bleeding therapy increased bleeding risk, there was still a net clinical benefit. .. risk.82,85,102,113 Similar differences in international guidance exist .. Vorapaxar was investigated in the TRA 2 P-TIMI 50 study, detailed in .. for AF patients with ACS treated with stent implant- Supplementary material online given the limited clinical use of this .. ation.55,56,116,117 The above applies to all individuals regardless .. agent.95–97 .. of DM status as no specific studies have been conducted in this .. In summary, following ACS, DAPT for 1 year is the current stand- .. group. A summary of the agents used in patients with AF and ard of care. De-escalation of DAPT intensity or duration may be con- .. ACS is provided in Figure 2. .. sidered after 3 months if bleeding concerns prevail.98 One year post- .. ACS, options include switching to aspirin monotherapy or, in high is- .. .. chaemic and low bleeding risk DM patients, continuation of dual .. Peripheral artery disease antithrombotic therapy in the form of aspirin and low-dose ticagrelor .. .. 118 (PEGASUS-TIMI 54 study) or aspirin and very-low-dose rivaroxaban .. PAD is thought to affect 202 million people worldwide and these (COMPASS trial).3,51,85 Studies addressing antithrombotic agents for .. individuals are at a higher MACE risk,119 with an even higher event .. secondary prevention are summarized in Table 2 and Supplementary .. rate with two or more arterial beds affected.119,120 material online, Figure S1. .. .. .. Asymptomatic peripheral artery disease Antithrombotic therapy in the presence .. .. Two relatively small trials have compared aspirin vs. placebo in of atrial fibrillation .. asymptomatic PAD, the POPADAD trial44 specific to DM and the .. Individuals with DM have a 40% greater risk of developing atrial fibril- .. AAA trial,121 which included 3% (n = 88) of DM patients. Neither lation (AF) compared to those without DM.99,100 Whilst epidemio- .. showed a difference in MACE in a combined overall cohort of 4626 .. logical data suggest a causal association, the effect of confounders .. patients (1256 with DM). While it can be argued these studies were cannot be excluded (further discussed in Supplementary material .. underpowered, guidelines generally do not support routine antiplate- .. online, S1).101–109 .. let therapy for asymptomatic lower extremity arterial disease and .. these individuals are best managed as per primary prevention recom- .. Antithrombotic therapy .. mendations described above. .. Oral anticoagulation (OAC) is recommended for male and female .. AF patients with CHA2DS2-VASc score >_2 and >_3, respectively, but .. Symptomatic peripheral artery disease can also be considered in those with lower scores on an individual ... A meta-analysis of 17 000 individuals with symptomatic PAD has .. basis.51 In those without absolute indication for VKAs (e.g. mechanic- .. shown that aspirin reduced serious vascular events by 18.2% per year al valve or moderate/severe mitral stenosis), NOACs are preferred .. (P < 0.0001), marginally offset by a non-significant increase in haemor- .. due to lower rates of severe bleeding and reduced monitoring .. rhagic stroke.42 requirements.51,110 In studies comparing NOACs with VKA in non- .. Subgroup analysis of 6452 patients with PAD (21% with DM) in .. valvular AF, about a third of individuals had DM and showed similar .. the CAPRIE study showed potentially greater benefit with clopidog- RRR to those without DM.111 However, given the increased risk in .. rel vs. aspirin [3.71% vs. 4.86%; RRR 24% (8.9–36.2); P = 0.0028] com- .. DM, therapy with NOACs translated into a greater absolute benefit, .. pared with the overall study population [5.32% vs. 5.83%; RRR 8.7% .. while rates of major bleeding are similar regardless of DM status. If .. (0.3–16.5); P = 0.043].86 The EUCLID trial compared ticagrelor and OAC is contraindicated, percutaneous left atrial appendage closure is .. clopidogrel in 13 885 patients with symptomatic PAD (38.4% with .. an option in those with or without DM.112 .. DM), finding no difference in MACE [10.8% vs. 10.6%, HR 1.02 (0.92– .. 1.13); P = 0.65] or major bleeding over a median follow-up of .. Antithrombotic therapy in patients with atrial fibrillation and acute cor- .. 30 months, regardless of DM status.122 onary syndrome .. A subgroup analysis of PAD patients in the CHARISMA trial .. Patients with AF on OAC who develop ACS and/or undergo PCI .. (n = 3096, 36.2% with DM) showed no significant difference in MACE generally require combination treatment with OAC and antiplatelet .. comparing aspirin and clopidogrel therapy with aspirin and placebo .. therapy, with NOACs preferred over VKA.82,85,113 For TT with .. [7.6% vs. 8.9%, HR 0.85 (0.66–1.08); P = 0.18], similar to the overall OAC and DAPT, clopidogrel is recommended over more potent .. trial cohort [6.8% vs. 7.3%, HR 0.93 (0.83–1.05); P = 0.22].123 There .. P2Y12 inhibitors.82,85,113 .. was an increase in minor bleeding with DAPT [34.4% vs. 20.8%, odds After elective PCI in patients with AF who require OAC, a .. ratio 1.99 (1.69–2.34); P < 0.001] but no difference in severe/moder- .. switch from TT (DAPT and OAC) to dual therapy (OAC and .. ate bleeding. The role of vorapaxar in PAD is described in the single antiplatelet therapy) should be considered in those at low .. Supplementary material online.124 .. risk of stent thrombosis or when bleeding risk is high. North .. A systematic review and network meta-analysis reported that as- American guidance encourages dual therapy with early aspirin .. pirin, ticlopidine, and ticagrelor or clopidogrel used as monotherapy 2244 Table 2 Secondary prevention in diabetes Sample Population Intervention Control Diabetes Primary Duration Relative and abso- Relative and abso- Comments size (%) endpoint of follow-up lute benefit lute harm ................................................................................................................................................................................................................................................................................................ CAPRIE (1996)86 19 185 Prior ischaemic stroke Clopidogrel (75 mg) Aspirin 20 Aggregate of MI, 1–3 years 5.32% vs. 5.83% GI bleed 1.99% vs. Treatment effect RCT (within 1 week– (325 mg) ischaemic RRR 8.7% 2.66%; P < 0.002 by subgroup 1:1 6 months), recent stroke, and vas- (0.30–16.5%); suggests het- MI (within 35 days), cular death P 5 0.043 erogeneity in or symptomatic response with atherosclerotic a benefit in PAD PAD, but not is post-MI or stroke patients DAPT (2014)88 9961 Prior coronary stent Thienopyridine (clopi- Placebo 30 (i) Stent 18 months (i) Stent throm- Moderate–severe RCT with DES after dogrel 65% or pra- thrombosis bosis 0.4% vs. bleeding 2.5% vs. 1:1 12 months of DAPT sugrel 35%) and 1.4%; HR 0.29 1.6%; P 5 0.001 (thienopyridine and (ii) MACCE (0.17–0.48); aspirin) (death, MI, or P < 0.001 stroke) (ii) MACCE 4.3% vs. 5.9% HR 0.71 (0.59–0.85); P < 0.001 PEGASUS-TIMI 54 21 162 MI 1–3 years earlier Ticagrelor 90 mg b.i.d. vs. placebo 32 Composite of CV 33 months 7.85% vs. 9.04% TIMI major No difference (2015)91 death, MI, or HR 0.85 (0.75– bleeding was detected RCT stroke 0.96); P 5 0.008 2.60% vs. 1.06%, in fatal or 1:1:1 P < 0.001 intracranial Ticagrelor 60 mg b.i.d. 7.77% vs. 9.04% TIMI major bleeding HR 0.84 (0.74– bleeding 0.95); P 5 0.004 2.30% vs. 1.06%; P < 0.001 TRA 2P-TIMI 50 26 449 History of MI, ischae- Vorapaxar (2.5 mg Placebo 25 Composite of 30 months 9.3% vs. 10.5% HR Moderate or se- Premature trial (2012)95 mic stroke, or PAD daily) death from CV 0.87 (0.80–0.94); vere bleeding termination at RCT causes, MI, or P < 0.001 4.2% vs. 2.5%, 2 years, due to 1:1 stroke HR 1.66 (1.43– safety con- 1.93); P < 0.001 cerns over Continued R.A. Ajjan et al. Antithrombotic therapy in diabetes Table 2 Continued Sample Population Intervention Control Diabetes Primary Duration Relative and abso- Relative and abso- Comments size (%) endpoint of follow-up lute benefit lute harm ................................................................................................................................................................................................................................................................................................ ICH ICH in patients 1.0% vs. 0.5%; with history of P < 0.001 stroke COMPASS (2017)92 27 395 Stable CAD, PAD, or Rivaroxaban (2.5 mg Aspirin 38 Composite of CV 23 months 4.1% vs. 5.4% Any bleeding Major bleeding RCT both b.i.d.) plus aspirin (100 mg/ death, stroke, HR 0.76 (0.66– 3.1% vs. 1.9% was not signifi- 1:1:1 (100 mg/day) day) or MI 0.86); P < 0.001 HR 1.70 (1.40– cantly different 2.05); P < 0.001 Rivaroxaban (5 mg 4.9% vs. 5.4% Any bleeding b.i.d.) HR 0.90 (0.79–1.03); 2.8% vs. 1.9% P = 0.12 HR 1.51 (1.25– 1.84); P < 0.001 Long-term therapy for secondary prevention trials in patients with established cardiovascular disease. This is a general guide and healthcare professionals should follow local guidelines as appropriate. Significant differences are highlighted in bold. b.i.d., twice daily; CAD, coronary artery disease; CV, cardiovascular; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; GI, gastrointestinal; HR, hazard ratio; ICH, intracranial haemorrhage; MACE, major adverse cardiovascular or cerebrovascular events; MI, myocardial infarction; PAD, peripheral arterial disease; RCT, randomized controlled trial; RRR, relative risk reduction. 2245 2246 R.A. Ajjan et al. .. (or in combination with aspirin) were effective in reducing MACE in .. DAPT still outweighed bleeding risk.135 The more recent THALES patients with PAD, and that ticlopidine, vorapaxar, and DAPT .. trial randomized 11 016 individuals (29% with diabetes), with ischae- .. increased bleeding risk.125 Clopidogrel had the best balance between .. mic stroke or TIA (NIHSS score <_5; 29% with DM) within 24 h of efficacy [MACE RRR 0.72 (0.58–0.91); NNT 80] and safety profile, .. presentation to DAPT with ticagrelor and aspirin or aspirin alone for .. making it the preferred agent to use. .. 30 days. The primary composite outcome of stroke or death at There were 7470 patients with PAD in the COMPASS trial, 44% .. 30 days occurred in 5.5% in the combination group vs. 6.6% in those .. of whom had DM with a median follow-up of 21 months.126 The .. on aspirin alone [HR 0.83 (0.71–0.96); P = 0.02] but incidence of dis- combination of rivaroxaban and aspirin reduced MACE and major .. ability showed no difference, while DAPT was associated with .. adverse limb events vs. aspirin alone to a similar degree in those with .. increased rate of severe bleeding (0.5% vs. 0.1%; P = 0.001).136 There DM [8% vs. 12%, HR 0.69 (0.53–0.91)] or without [5% vs. 7%, HR .. was no suggestion in any of the studies that the diabetes subgroup .. 0.69 (0.50–0.94)]. This was associated with a lower incidence of .. behaved differently and therefore DAPT in DM should be initiated major adverse limb events in the whole group [1% vs. 2%, HR 0.54 .. within 24 h following acute minor stroke not requiring thrombolysis .. (0.35–0.84); P = 0.005], including lower incidence of major amputa- .. or thrombectomy and continued for 21–30 days. Future work is tion [HR 0.30 (0.11–0.80); P = 0.011]. .. required to clarify the optimal duration of DAPT after acute minor .. .. stroke, or the benefit of DAPT following reperfusion therapy.132,137 Post-revascularization .. .. Limited evidence suggests that DAPT with aspirin and clopidogrel is .. Long-term non-cardioembolic stroke beneficial after lower limb revascularization, particularly following .. .. prevention prosthetic bypass.125,127 Similarly, warfarin, with or without aspirin, .. may improve graft patency after vein bypass.128,129 The VOYAGER .. The effect of aspirin on secondary prevention in stroke/TIA patients .. is well-established, as are the effects of clopidogrel and aspirin/dipyr- PAD trial, assessing aspirin plus rivaroxaban vs. aspirin post-lower .. .. idamole combination.138 The benefits of aspirin (75–150 mg daily) ap- limb revascularization, included 6564 individuals (40% had DM) and .. pear to be most pronounced in the first 6–12 weeks following the combination therapy reduced the composite of acute limb ischaemia, .. .. event, while combination with dipyridamole may offer better longer- major amputation, MI, ischaemic stroke, or cardiovascular death [HR .. term protection.139 Clopidogrel is as good as aspirin/dipyridamole 0.85 (0.76–0.96); P = 0.009]. A trend towards an increase in TIMI .. .. combination and is preferred for secondary prevention, particularly major bleeding, but not BARC bleeding, was documented with the .. with the frequent headaches with aspirin/dipyridamole combination combination therapy [HR 1.43 (0.97–2.10); P = 0.07].130 Results of .. .. leading to discontinuation.140,141 the DM subgroup analysis are awaited. Antithrombotic management .. DAPT for long-term use is discouraged as studies showed exces- of individuals with DM and PAD is summarized in Table 3 and .. .. sive bleeding without a vascular benefit.142–145 Supplementary material online, Figure S1. .. Taken together, for the management of DM individuals, aspirin is .. .. justified 24 h after an acute event requiring reperfusion therapy fol- .. Treatment of individuals with .. lowed by a switch to clopidogrel 3 months later (or continue aspirin .. while adding dipyridamole). In those not receiving reperfusion ther- cerebrovascular disease .. .. apy, DAPT can be immediately started (provided haemorrhagic .. stroke is ruled out) and continued for 21 days followed by long-term Due to lack of DM-specific studies, antithrombotic therapy in individ- .. uals sustaining a stroke is similar regardless of DM status and there- .. monotherapy with clopidogrel (or a combination of aspirin/dipyrid- .. amole), which applies to individuals with and without diabetes fore studies are discussed accordingly. .. .. (Figure 2).139–141 .. Following acute events .. .. Stroke prevention in association with In acute severe ischaemic stroke, reperfusion is attempted either .. through thrombolysis or endovascular thrombectomy, followed by .. non-valvular atrial fibrillation .. antiplatelet monotherapy, usually with aspirin, administered 24 h .. As discussed above, anticoagulation is recommended for those with later.131,132 Ticagrelor monotherapy showed no superiority over as- .. AF and elevated CHA2DS2-VASc score, of which DM is a .. pirin133 and, therefore, is only recommended if aspirin is .. component.113,146,147 contraindicated.132 .. Potential superior efficacy of NOACs, together with reduced .. In those with minor events [National Institute of Health Stroke .. bleeding events and reduced need for monitoring, offers distinct Scale (NIHSS) score <_3], high-risk transient ischaemic attack (TIA) .. advantages over VKAs. An analysis of four large RCTs [RE-LY, .. (ABCD2 score >_4) or TIA not requiring thrombolysis or invasive .. ARISTOTLE, ROCKET-AF, and ENGAGE AF-TIMI 48 (23%, 25%, measures, antiplatelet therapy can be immediately started provided .. 40%, and 36% with DM, respectively)],148–151 enrolling over 70 000 .. haemorrhagic stroke is excluded. DAPT (aspirin and clopidogrel) is .. patients with non-valvular AF with at least one additional risk factor recommended given findings from the CHANCE and POINT trials .. for stroke, demonstrated that dabigatran or factor Xa inhibitors .. (21% and 28% of the study population had diabetes, respective- .. (apixaban, rivaroxaban, edoxaban) are at least as efficacious as war- ly),134,135 starting within 24 h of the event for 21 days followed by clo- .. farin, and in some cases superior, in preventing stroke, whilst reduc- .. pidogrel only.132 While severe haemorrhagic events showed no .. ing bleeding risk. Sub-analysis of DM patients in these trials showed increase in CHANCE, a doubling was noticed in POINT (Table 4 and .. similar anti-thrombotic benefits of NOACs but bleeding risk reduc- .. Supplementary material online, Figure S1), although the benefit of . tion appeared to be attenuated.152–154 Table 3 Antithrombotic therapy in peripheral vascular disease Trial Sample size Population Investigation Control % with Follow-up Outcomes Absolute and relative Absolute and relative Other comments diabetes benefits harms ................................................................................................................................................................................................................................................................................................ Asymptomatic POPADAD 1276 Type 1 or 2 diabetes melli- Aspirin 100 mg ± Placebo ± 100% Median MACCE or above 18.2% vs. 18.3% GI bleed (2008)44 tus and ABPI <_0.99 with antioxidant antioxidant 6.7 years ankle amputation HR 0.98 (0.76–1.26); 4.4% vs. 4.9% Antithrombotic therapy in diabetes no PAD symptoms for critical limb P = 0.86 HR 0.90 (0.53–1.52); ischaemia P = 0.69 AAA (2010)121 3350 ABPI <_0.95; free from clin- Aspirin 100 mg Placebo 3% Mean MACCE or 13.7 vs. 13.3 events/1000 Major bleed ical CV disease 8.2 years revascularization person-years 2.0% vs. 1.2% HR 1.03 (0.84–1.27) HR 1.71 (0.99–2.97) Symptomatic ATT Collaboration 17 000 Meta-analysis of secondary Aspirin 75– No aspirin Not stated NA MACCE 6.7% vs. 8.2% per year; Major extracranial bleed Non-significant increase (2009)42 prevention trials (not 500 mg HR 0.81 (0.75–0.87); (incompletely reported) haemorrhagic stroke, PAD specific) P < 0.0001 23 vs. 6 events significant decrease is- HR 2.69 (1.25–5.76) chaemic stroke and coronary events CAPRIE (1996)86 6452 Symptomatic PAD and Clopidogrel 75 mg Aspirin 325 mg 21% Mean MACCE 3.71% vs. 4.86% per GI bleed 1.99% vs. No difference in amputa- ABPI <_0.85; or symp- 1.9 years year; 2.66%; P < 0.002 (for tion rate across tomatic PAD with previ- RR 23.8% (8.9–36.2); the whole group) CAPRIE cohorts; not ous amputation or P 5 0.0028 reported specific to revascularization PAD subgroup EUCLID (2017)122 13 885 PAD with ABPI <_0.8 or Ticagrelor 90 mg Clopidogrel 75 mg 38% Median MACCE 10.8% vs. 10.6% TIMI major bleeding previous lower limb b.i.d. 30 months HR 1.02 (0.92–1.13); 1.6% vs. 1.6% revascularization P = 0.65 HR 1.10 (0.84–1.43); >30 days before Lower limb 12.2% vs. 12.8% P = 0.49 randomization revascularization HR 0.95 (0.87–1.05); P = 0.30 CHARISMA 3096 Symptomatic PAD and Aspirin Aspirin 36% Median MACCE 7.6% vs. 8.9% Severe bleeding Non-significant trend to- subgroup PAD (2838 symptomatic, ABPI <_0.85; or symp- 75–162 mg þ clo- 75–162 mg þ 28 months HR 0.85 (0.66–1.08); 1.7% vs. 1.7% wards increase of fatal, (2009)123 258 asymptomatic) tomatic PAD with previ- pidogrel placebo P = 0.183 HR 0.97 (0.56–1.66); intracranial, and mod- ous amputation or 75 mg (DAPT) P = 0.90 erate bleeding with revascularization; Minor bleeding 34.4% vs. DAPT asymptomatic with APBI 20.8% <0.9 identified within HR 1.99 (1.69–2.34); those with other eligibil- P < 0.001 ity for CHARISMA study Continued 2247 2248 Table 3 Continued Trial Sample size Population Investigation Control % with Follow-up Outcomes Absolute and relative Absolute and relative Other comments diabetes benefits harms ................................................................................................................................................................................................................................................................................................ TRA2 P-TIMI 50 3787 Symptomatic PAD and Vorapaxar 2.5 mg Placebo 36% Median MACCE 11.3% vs. 11.9% GUSTO moderate/severe (2013)124 ABPI <0.85 or previous 36 months HR 0.94 (0.78–1.14); bleeding: lower limb P = 0.53 7.4% vs. 4.5% revascularization Acute limb ischaemia 2.3% vs. 3.9% HR 1.62 (1.21–2.18); HR 0.58 (0.39–0.86); P 5 0.001 P 5 0.006 Revascularization 18.4% vs. 22.2% HR 0.84 (0.73–0.97); P 5 0.017 COMPASS 7470 Previous lower limb revas- Rivaroxaban Aspirin 100 mg þ 44% Median MACCE 5% vs. 7% Major bleeding 3.1% vs. (2018)126 (4129 symptomatic cularization or amputa- 2.5 mg b.i.d þ placebo 21 months HR 0.72 (0.57–0.90); 1.9% lower limb; 1422 tion; symptomatic PAD aspirin 100 mg P 5 0.005 HR 1.61 (1.12–2.31); asymptomatic and ABPI <0.9 or sten- Major adverse limb 1.2% vs. 2.2% P 5 0.009 lower limb; 1919 osis >_50% on arterial event (acute/chron- HR 0.54 (0.35–0.84); carotid disease) imaging; carotid revascu- ic ischaemia; P 5 0.005 larization or asymptom- amputation) atic carotid artery stenosis >_50% Post-revascularization CASPAR (2010)127 851 Vascular bypass graft for Aspirin 75– Aspirin 75– 38% Median Graft occlusion/revas- All grafts Total bleeding Graft occlusion treatment of PAD 100 mg þ clo- 100 mg þ 12 months cularization/ampu- 35.4% vs. 35.0% 16.7% vs. 7.1%; P < 0.001 HR 0.63 (0.42–0.93) and pidogrel 75 mg placebo tation/death HR 0.98 (0.78–1.23) Severe bleeding amputation (DAPT) Venous 2.1% vs. 1.2%; P = NS HR 0.48 (0.24–0.96) sig- 23.8% vs. 20.0% nificantly reduced in HR 1.25 (0.94–1.67) prosthetic but not Prosthetic vein bypass 37.5% vs. 52.8% Continued R.A. Ajjan et al. Table 3 Continued Antithrombotic therapy in diabetes Trial Sample size Population Investigation Control % with Follow-up Outcomes Absolute and relative Absolute and relative Other comments diabetes benefits harms ................................................................................................................................................................................................................................................................................................ HR 0.65 (0.45–0.95); P 5 0.025 BOA (2000)128 2690 Infrainguinal bypass graft Oral anticoagu- Pulverized carba- 26% Mean Occlusion 23.2% vs. 24.3% Total bleeding Fatal intracranial bleeding for obstructive arterial lants (target salate calcium 21 months HR 0.95 (0.82–1.11) 119 vs. 59 events events were higher (8 disease INR 3.0–4.5) 100 mg MACE plus 18.7% vs. 20.8% Fatal bleeding vs. 3 events) in oral (equivalent to amputation HR 0.89 (0.75–1.06) 16 vs. 12 events anticoagulants, where- aspirin 80 mg) Vein graft occlusion 14.3% vs. 20.3% Gastrointestinal bleeding as bleeding events in HR 0.69 (0.54–0.88) 51 vs. 29 events other sites were similar Non-vein grafts 36% vs. 30% Intracranial bleeding between groups occlusion HR 1.26 (1.03–1.55) 18 vs. 4 events Sarac et al. 56 Infrainguinal bypass with Warfarin (target Aspirin 325 mg 64% Not stated 30-day graft patency 97.3% vs. 85.2%; P = 0.07 Haematoma (1998)129 autogenous vein and INR 2–3) þ as- (outcomes 30-day amputation 0% vs. 11.1%; P 5 0.04 32% vs. 4%; P 5 0.004 deemed high risk for pirin 325 mg derived from rate GI bleeding graft occlusion (subopti- Kaplan–Meier 3-year primary 77% vs. 56%; P = 0.05 3% vs. 11%; P = NS mal venous conduit, survival assisted patency: Intracranial bleeding poor arterial runoff or curves) 3-year secondary 81% vs. 56%; P 5 0.02 3% vs. 4%; P = NS redo bypass) patency VOYAGER-PAD 6564 Post-lower limb Rivaroxaban Aspirin 100 mg þ 40% Median 28 months MACE plus acute limb 15.5% vs. 17.8% Major bleeding (2020)130 revascularization 2.5 mg b.i.d. þ placebo ischaemia or HR 0.85 (0.76–0.96) 1.9% vs. 1.35% aspirin 100 mg amputation HR 1.43 (0.97–2.10); P = 0.07 Summary of antiplatelet and anticoagulant studies in individuals with peripheral vascular disease. Significant differences are highlighted in bold. ABPI, ankle brachial pressure index; b.i.d., twice daily; CV, cardiovascular; DAPT, dual antiplatelet therapy; GI, gastrointestinal; HR, hazard ratio; INR, international normalized ratio; MACE, major adverse cardiovascular or cerebrovascular events; NA, not available; PAD, peripheral artery disease. 2249 Table 4 Antithrombotic therapy in cerebrovascular disease 2250 Antiplatelet randomized trial for secondary prevention in patients with acute minor ischaemic stroke/high-risk TIA ................................................................................................................................................................................................................................................................................................ Study Patients Intervention Control Follow-up Composite vascular Recurrent ischaemic Intracranial Major haemorrhage events (stroke, MI or stroke haemorrhage CVD death) ................................................................................................................................................................................................................................................................................................ CHANCE (2013)134 Minor stroke (NIHSS Clopidogrel 300 mg loading Clopidogrel 75 mg/day 90 days 8.4% vs. 11.9% 7.9% vs. 11.4% 0.3% vs. 0.3% 0.2% vs. 0.2% (N = 5170; 21.1% with DM) <3)/high-risk TIA, then 75 mg/day on days on days 1–90 HR 0.69 (0.58–0.82) HR 0.67 (0.56–0.81) HR 1.01 (0.38–2.70) HR 0.94 (0.24–3.79) onset <24 h 2–90 (haemorrhagic stroke) (severe bleeding) Aspirin 75–300 mg/day on 0.1% vs. 0.2% days 2–21 HR 0.73 (0.16–3.26) (moderate bleeding) POINT (2018)135 Minor stroke (NIHSS Clopidogrel 600 mg loading Aspirin 50–325 mg on 90 days 5.0% vs. 6.5% 4.6% vs. 6.3% 0.2% vs. 0.1% 0.9% vs. 0.4% (N = 4881; 27.5% with DM) <3)/high-risk TIA, then 75 mg/day on days days 1–90 HR 0.75 (0.59–0.95) HR 0.72 (0.56–0.92) HR 1.68 (0.40–7.03) HR 2.32 (1.10–4.87) onset <12 h 2–90 (recommend 162 mg/day (haemorrhagic stroke) Aspirin 50–325 mg/day on on day 1–5, then days 2–21 81 mg/day afterward) SOCRATES (2016)133 Non-severe stroke Ticagrelor 180 mg loading Aspirin 300 mg loading 90 days 6.5% vs. 7.2% 5.9% vs. 6.6% 0.2% vs. 0.3% 0.5% vs. 0.6% (N = 6589; 24.3% with DM) (NIHSS <5)/high-risk then 90 mg b.i.d. on days then 100 mg/day on HR 0.89 (0.78–1.01) HR 0.87 (0.76–1.00) HR 0.68 (0.33–1.41) HR 0.83 (0.52–1.34) TIA, onset <24 h 2–90 days 2–90 THALES (2020)136 Mild–moderate stroke Ticagrelor 180 mg loading Aspirin 300–325 mg load- 30 days 5.5% vs. 6.6% 5.0% vs. 6.3% 0.4% vs. 0.1% 0.5% vs. 0.1% (N = 11 016; 28.6% with DM) (NIHSS <5)/high-risk then 90 mg b.i.d. on days ing then 75–100 mg HR 0.83 (0.71–0.96) HR 0.79 (0.68–0.93) HR 3.33 (1.34–8.28) HR 3.99 (1.74–9.14) TIA (ABCD2 > 6), 2–30 o.d. on days 2–30 (stroke or death) onset <24 h Aspirin 300–325 mg loading then 75 to 100 mg/day on days 2–30 Anti-platelet randomized trials for long-term secondary prevention in patients with previous non-cardioembolic ischaemic stroke/TIA ................................................................................................................................................................................................................................................................................................ Study Patient Intervention Control Follow-up Non-fatal MI, non- Recurrent ischaemic Intracranial Major haemorrhage fatal stroke, death stroke haemorrhage from vascular causes ................................................................................................................................................................................................................................................................................................ CAPRIE (1996)86 Recent MI, PAD, or Clopidogrel 75 mg/day Aspirin 325 mg/day 1.9 years 5.32% vs. 5.83% Not reported 0.35% vs. 0.49% 1.38% vs. 1.55% (N = 19 185; 20% with DM) stroke HR 0.91 (0.84–1.00) (severe bleeding) CAPRIE (1996)86 stroke subgroup Recent stroke Clopidogrel 75 mg/day Aspirin 325 mg/day 7.15% vs. 7.71% 5.2% vs. 5.7% Not reported Not reported (N = 6431; 25% with DM) HR 0.91 (0.81–1.06) ESPRIT (2006)140 Recent minor stroke/TIA Dipyridamole 200 mg b.i.d. Aspirin 30–325 mg/day 3.5 years 3.3% vs. 4.3% 2.1% vs. 2.6% 0.8% vs. 1.5% 2.5% vs. 3.9% (N = 2739; 18.7% with DM) (mRS <3) within plus (median 75 mg/day) HR 0.78 (063–097) HR 0.84 (0.64–1.10) 6 months Aspirin 30–325 mg/day (median 75 mg/day) PRoFESS (2008)141 Recent stroke within Extended release dipyrid- Clopidogrel 75 mg/day 2.5 year 13.1% vs. 13.1% 7.7% vs. 7.9% 1.4% vs. 1.0% 4.1% vs. 3.6% (N = 20 332; 28% with DM) 90 days amole 200 mg b.i.d. HR 0.99 (0.92–1.07) HR 0.97 (0.88–1.07) HR 1.42 (1.11–1.83) HR 1.15 (1.00–1.32) plus Continued R.A. Ajjan et al. Table 4 Continued Anti-platelet randomized trials for long-term secondary prevention in patients with previous non-cardioembolic ischaemic stroke/TIA ................................................................................................................................................................................................................................................................................................ Study Patient Intervention Control Follow-up Non-fatal MI, non- Recurrent ischaemic Intracranial Major haemorrhage fatal stroke, death stroke haemorrhage from vascular causes ................................................................................................................................................................................................................................................................................................ Aspirin 25 mg b.i.d. MATCH (2004)145 Recent stroke/TIA within Clopidogrel 75 mg/day Clopidogrel 75 mg/day 1.5 years 16% vs. 17% 8% vs. 9% 1.1% vs. 0.7% 1.9% vs. 0.6% (N = 7599; 68% with DM) 3 months plus HR 0.94 (0.84–1.05) HR 0.93 (0.80–1.09) (P < 0.001) Antithrombotic therapy in diabetes plus >1 risk factors Aspirin 75 mg/day CHARISMA (2006)142 Atherosclerotic risks, Clopidogrel 75 mg/day Aspirin 75–162 mg/day 2.3 years 6.8% vs. 7.3% 1.7% vs. 2.1% 0.3% vs. 0.3% 2.1% vs. 1.3% (N = 15 603; 42.7% with DM) CVD, stroke/TIA with- plus HR 0.93 (0.83–1.05) HR 0.81 (0.64–1.02) HR 0.96 (0.56–1.65) HR 1.62 (1.27–2.08) in 5 years Aspirin 75–162 mg/day SPS3 (2012)143 Symptomatic lacuna Clopidogrel 75 mg/day Aspirin 325 mg/day 3.4 years 3.1% vs. 3.4% 2.0% vs. 2.4% 0.4% vs. 0.3% 2.1% vs. 1.1% (N = 3020; 36.5% with DM) stroke within plus HR 0.89 (0.72–1.11) HR 0.82 (0.63–1.09) HR 1.65 (0.83–3.31) HR 1.97 (1.41–2.71) 6 months Aspirin 325 mg/day Greving et al. (2019)144 Meta-analysis (6 RCTs) Clopidogrel Aspirin 2.0 years 0.88 (0.78–0.98) 0.91 (0.81–1.02) 0.63 (0.43–0.91) 0.76 (0.63–0.91) (N = 43 112; 33.3% with DM) Aspirin/dipyridamole 0.83 (0.74–0.94) 0.86 (0.76–0.97) 0.88 (0.60–1.31) 0.86 (0.71–1.05) Aspirin/clopidogrel 0.83 (0.71–0.96) 0.83 (0.71–0.97) 1.19 (0.68–2.08) 1.63 (1.29–2.07) Aspirin/dipyridamole Clopidogrel 0.95 (0.85–1.06) 0.95 (0.87–1.04) 1.40 (1.08–1.82) 1.14 (1.00–1.30) Aspirin/clopidogrel 0.94 (0.82–1.08) 0.91 (0.80–1.04) 1.88 (1.12–3.16) 2.16 (1.72–2.71) Aspirin/clopidogrel Aspirin/dipyridamole 0.99 (0.84–1.17) 0.96 (0.82–1.13) 1.34 (0.77–2.36) 1.89 (1.47–2.42) Anti-coagulant randomized trials for primary and secondary preventions in patients with atrial fibrillation ................................................................................................................................................................................................................................................................................................ Study Patients Intervention Control Follow-up Stroke or systemic Ischaemic stroke Intracranial Major haemorrhage embolic event haemorrhage ................................................................................................................................................................................................................................................................................................ ARISTOTLE (2011)149 Patients with AF Apixaban 5 mg b.i.d. Warfarin (keep INR 2.0– 2 years 1.27% vs. 1.60% 0.97% vs. 1.05% 0.33% vs. 0.80% 2.13% vs. 3.09% (N = 18 201; 25% with CHADS2 >1 Apixaban 2.5 mg b.i.d. in 3.0) HR 0.79 (0.66–0.95) HR 0.92 (0.74–1.13) HR 0.42 (0.30–0.58) HR 0.69 (0.60–0.80) DM) age >80 years, body ARISTOTLE (2015)153 DM patients were younger, weight <60 kg, cre- 1.39% vs. 1.86% Not reported 0.34% vs. 0.70% 3.01% vs. 3.13% DM subgroup more CAD, higher atinine >1.5 mg/mL HR 0.75 (0.53–1.05) HR 0.49 (0.25–0.95) HR 0.96 (0.74–1.25) (N = 4547) CHADS2 and HAS- BLED RE-LY (2009)148 Patients with AF Dabigatran 110 mg b.i.d. Warfarin (keep INR 2.0– 2 years 1.53% vs. 1.69% 1.34% vs. 1.20% 0.23% vs. 0.74% 2.71% vs. 3.36% (N = 18 113; 23.3% with CHADS2 >1 3.0) HR 0.91 (0.74–1.11) HR 1.11 (0.89–1.40) HR 0.31 (0.20–0.47) HR 0.80 (0.69–0.93) DM) or Dabigatran 150 mg b.i.d. 1.11% vs. 1.69% 0.92% vs. 1.20% 0.3% vs. 0.74% 3.11% vs. 3.36% CHA2DS2-VASc >2 for HR 0.66 (0.53–0.82) HR 0.76 (0.60–0.98) HR 0.40 (0.27–0.60) HR 0.93 (0.81–1.07) men or >3 for women RE-LY (2015)152 DM patients were younger, Dabigatran 110 mg b.i.d. Warfarin (keep INR 2.0– 1.76% vs. 2.35% 1.62% vs. 1.65% 0.22% vs. 0.81% 3.81% vs. 4.19% DM subgroup more CAD and PAD, 3.0) HR 0.74 (0.51–1.07) HR 0.97 (0.64–1.40) HR 0.26 (0.11–0.65) HR 0.91 (0.70–1.19) (N = 4221) higher CHA2DS2VASc Dabigatran 150 mg b.i.d. 1.46% vs. 2.35% 1.28% vs. 1.65% 0.47% vs. 0.81% 4.66% vs. 4.19% scores HR 0.61 (0.41–0.91) HR 0.76 (0.49–1.19) HR 0.58 (0.29–1.16) HR 1.12 (0.87–1.44) 2251 Continued Table 4 Continued 2252 Anti-coagulant randomized trials for primary and secondary preventions in patients with atrial fibrillation ................................................................................................................................................................................................................................................................................................ Study Patients Intervention Control Follow-up Stroke or systemic Ischaemic stroke Intracranial Major haemorrhage embolic event haemorrhage ................................................................................................................................................................................................................................................................................................ ROCKET AF (2011)150 Patients with AF Rivaroxaban 20 mg/day Warfarin (keep INR 2.0– 1.9 years 1.7% vs. 2.2% 2.11% vs. 2.27% 0.8% vs. 1.2% 5.6% vs. 5.4% (N = 14 264; 39.9% with CHADS2 >2 (15 mg/day if creatinine 3.0) HR 0.79 (0.66–0.96) HR 0.94 (0.75–1.17) HR 0.67 (0.47–0.93) HR 1.04 (0.90–1.20) DM) clearance 30–49 mL/ ROCKET AF (2015)154 DM patients were younger, min) 1.7% vs. 2.1% 1.35% vs. 1.45% 0.5% vs. 0.8% 3.8% vs. 3.9% DM subgroup more obese, higher BP, HR 0.82 (0.63–1.08) HR 0.94 (0.69–1.30) HR 0.62 (0.36–1.05) HR 1.00 (0.81–1.24) (N = 5695) similar CHADS2 scores ENGAGE AF-TIMI 48 Patients with AF Edoxaban 30 mg/day Warfarin (keep INR 2.0– 2.8 years 1.61% vs. 1.50% 1.77% vs. 1.25% 0.26% vs. 0.85% 1.61% vs. 3.43% (2013)151 CHADS2 >2 (15 mg/day if creatinine 3.0) HR 1.07 (0.87–1.31) HR 1.41 (1.19–1.67) HR 0.30 (0.21–0.43) HR 0.47 (0.41–0.55) (N = 21 105; 36.1% with clearance 30–50 mL/ DM) min, body weight <60 kg, or concomi- tant use of verapamil or quinidine) Edoxaban 60 mg/day 1.18% vs. 1.50% 1.25% vs. 1.25% 0.39% vs. 0.85% 2.75% vs. 3.43% (30 mg/day if creatinine HR 0.79 (0.63–0.99) HR 1.00 (0.83–1.19) HR 0.47 (0.34–0.63) HR 0.80 (0.71–0.91) clearance 30–50 mL/ min, body weight <60 kg, or concomi- tant use of verapamil or quinidine) Antiplatelet platelet and anticoagulant for secondary prevention in atrial fibrillation patients ineligible for vitamin K antagonist ................................................................................................................................................................................................................................................................................................ Study Patients Intervention Control Follow-up Stroke, systemic Ischaemic stroke Intracranial Major haemorrhage emboli, MI, CVD haemorrhage death ................................................................................................................................................................................................................................................................................................ AVERROES (2011)155 Patients with AF Apixaban 5 mg b.i.d. Aspirin 81–324 mg/day 1.1 years 4.2% vs. 6.4% 1.1% vs. 3.0% 0.4% vs. 0.4% 1.4% vs. 1.2% (N = 5599; 19.6% with Ineligible for VKA Apixaban 2.5 mg b.i.d. in HR 0.66 (0.53–0.83) HR 0.37 (0.25–0.55) HR 0.85 (0.38–1.90) HR 1.13 (0.74–1.75) DM) CHADS2 >1, or docu- age >80 years, body mented PAD weight <60 kg, creatin- ine >1.5 mg/mL Antiplatelet and anticoagulant studies for secondary prevention in individuals with cerebrovascular disease. Significant differences are highlighted in bold. b.i.d., twice daily; CAD, coronary artery disease; CHA2DS2-VASc, score, Congestive Heart failure, hypertension, Age >_75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65–74, and Sex (female); CHADS2 score, Cardiac fail- ure, Hypertension, Age, Diabetes, Stroke (doubled); CVD, cardiovascular disease; DM, diabetes mellitus; HAS-BLED score, hypertension, abnormal renal/liver function (1 point each), stroke, bleeding history or predisposition, labile INR, elderly (65 years), drugs/alcohol concomitantly (1 point each); HR, hazard ratio; MI, myocardial infarction; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; PAD, peripheral artery disease; TIA, transient ischae- mic stroke; VKA, vitamin K antagonist. R.A. Ajjan et al. Antithrombotic therapy in diabetes 2253 In AF patients who are ineligible for VKA, apixaban (AVERROES .. rather than subgroup, and often post hoc, analyses of cardiovascular .. trial; 20% with diabetes) is the only NOAC that has demonstrated su- .. trials designed for the wider population (DM-specific studies are perior efficacy to aspirin in preventing MACE (stroke, systemic em- .. summarized in Supplementary material online, Table S3 and gaps in .. bolism, MI, and vascular death) with similar bleeding risk in the whole .. knowledge/future work in Supplementary material online, Table S4). study population with no subgroup analysis conducted for those with .. This will require greater collaboration between metabolic and vascu- .. DM.155 .. lar medical disciplines to design appropriate studies aiming to reduce In summary, current evidence supports OAC in DM individuals .. vascular events and improve clinical outcomes in the high-risk DM .. with AF with or without a history of stroke who fulfil treatment crite- .. population. .. ria and do not have excessive bleeding risk. NOACs are preferable .. to VKAs in eligible patients. .. .. Timing of initiation (or therapy resumption) of OAC in AF patients .. Supplementary material suffering an acute stroke is a challenging area. Based largely on two .. .. studies, RAF and RAF-NOACs,156,157 the American Heart .. Supplementary material is available at European Heart Journal online. Association/American Stroke Association 2018/2019 guidelines rec- .. .. ommend starting OAC within 4–14 days of an acute ischaemic .. Funding stroke.132 The European Heart Rhythm Association-ESC guidelines .. N.K. is funded by Faculty of Medicine, Prince of Songkla University, .. give a more structured recommendation with the ‘1–3–6–12 days .. Thailand. Research work in Ajjan’s laboratory is funded by the National rule’.158 In brief, OAC should be initiated or reinstated after 1 day for .. Institute for Health Research, Diabetes UK, British Heart Foundation, .. TIA, 3 days for mild stroke (NIHSS score <8), 6 days for moderate .. Biotechnology and Biological Sciences Research Council, Abbott stroke (NIHSS score 8–15), and 12 days for severe stroke (NIHSS .. Diabetes Care and Avacta Life Sciences. .. score >_16). These recommendations are based solely on expert con- .. Conflict of interest: R.A.A. reports grants, personal fees and other sensus without robust RCTs supporting this approach. Of note, .. .. from Abbott Diabetes Care, personal fees from AstraZeneca, personal bridging with full-dose low-molecular-weight heparin before or to- .. fees from Boehringer Ingelheim, personal fees from Eli Lilly, personal fees gether with VKA is not recommended.159 Table 4 summarizes key .. from Menarini Pharmaceuticals, personal fees from Novo Nordisk, out- .. studies on antithrombotic agents in cerebrovascular disease. .. side the submitted work; N.K. has nothing to disclose; L.B. reports grants .. from AstraZeneca, the European Union-IMI and -H2020, Carlos III .. .. Institute of Health-Spain, and CIBERCV-Spain; personal fees (scientific ad- .. visory boards/speaker fees) from AstraZeneca, Lilly, BMS/Pfizer, Conclusions and future directions .. SANOFI, BAYER, International Aspirin Foundation, Glycardial SL, PACE .. .. and FICYE, all outside the submitted work; G.V. reports grants from While a large number of studies investigated the best antithrombotic .. AstraZeneca, outside the submitted work; D.A.G. reports personal fees strategy in vascular disease patients, there is still a distinct lack of DM- .. .. and other from Astra Zeneca, grants from Bayer, personal fees from specific RCTs, particularly for secondary prevention. The heteroge- .. Boehringer Ingelheim, outside the submitted work; D.J.A. reports grants neous vascular risk in DM patients, which can vary in the same indi- .. and personal fees from Amgen, grants and personal fees from Aralez, .. vidual according to DM duration and development of complications, .. grants and personal fees from Bayer, grants and personal fees from adds to the complexity and prevents guidelines from making con- .. Biosensors, grants and personal fees from Boehringer Ingelheim, grants .. crete recommendations. For example, advanced renal disease may .. and personal fees from Bristol-Myers Squibb, grants and personal fees alter both thrombosis and bleeding risk and may even limit the use of .. from Chiesi, grants and personal fees from Daiichi-Sankyo, grants and .. personal fees from Eli Lilly, personal fees from Haemonetics, grants and some antithrombotic therapies.33 The increased weight in DM indi- .. .. personal fees from Janssen, grants and personal fees from Merck, person- viduals may also affect the response to antithrombotic agents, .. al fees from PhaseBio, personal fees from PLx Pharma, personal fees from reviewed elsewhere.160 A key difficulty remains the lack of bio- .. .. Pfizer, grants and personal fees from Sanofi, personal fees from the marker(s) that accurately predicts thrombotic/bleeding risk and re- .. Medicines company, grants and personal fees from CeloNova, personal sponse to therapy. .. fees from St Jude Medical, grants from CSL Behring, grants from Eisai, .. Given current knowledge, primary prevention with antiplatelet .. grants from Gilead, grants from Idorsia Pharmaceuticals Ltd, grants from agents, mainly aspirin, may only be considered in higher-risk individu- .. Matsutani Chemical Industry Co., grants from Novartis, grants from .. als. Following ACS, DAPT is necessary using aspirin and ticagrelor or .. Osprey Medical, grants from Renal Guard Solutions, grants from Scott R. prasugrel, usually for 12 months but also longer term with aspirin and .. MacKenzie Foundation, grants and personal fees from Astra Zeneca, out- .. side the submitted work; D.R. has nothing to disclose; B.R. reports per- ticagrelor in high thrombotic risk patients. In stable atherosclerotic .. disease, the combination of aspirin and very-low-dose rivaroxaban is .. sonal fees from Novartis, personal fees from Medscape, grants from .. Bayer AG, grants from Italian Medicines Agency, outside the submitted useful, particularly in the presence of PAD (Figure 2).161 In individuals .. with stroke, the choice of antithrombotic therapy is dictated by .. work; R.F.S. reports personal fees from Bayer, personal fees from Bristol- .. Myers Squibb/Pfizer, grants and personal fees from AstraZeneca, grants whether the individual required reperfusion and the presence of AF .. and personal fees from Thromboserin, personal fees from Haemonetics, (Figure 2 and Graphical Abstract). .. .. personal fees from Amgen, grants and personal fees from Glycardial Areas for future research include the development of reliable bio- .. Diagnostics, personal fees from Portola, personal fees from Medscape, markers and/or in silico model, able to assess thrombotic risk and re- .. grants and personal fees from Cytosorbents, personal fees from Intas .. sponse to therapy. Moreover, DM-specific studies are warranted . Pharmaceuticals, personal fees from Hengrui, personal fees from Sanofi 2254 R.A. Ajjan et al. Aventis, personal fees from Idorsia, personal fees from PhaseBio, outside .. microRNA expression in platelets to increase P2RY12 and SELP levels in type 2 .. diabetes mellitus. Thromb Haemost 2017;117:529–542. the submitted work. .. .. 19. Pordzik J, Jakubik D, Jarosz-Popek J, Wicik Z, Eyileten C, De Rosa S, Indolfi C, References .. Siller-Matula JM, Czajka P, Postula M. Significance of circulating microRNAs in .. diabetes mellitus type 2 and platelet reactivity: bioinformatic analysis and re- 1. Emerging Risk Factors Collaboration; Di Angelantonio E, Kaptoge S, Wormser .. view. Cardiovasc Diabetol 2019;18:113. D, Willeit P, Butterworth AS, Bansal N, O’Keeffe LM, Gao P, Wood AM, .. 20. Gawaz M, Ott I, Reininger AJ, Neumann FJ. Effects of magnesium on platelet ag- Burgess S, Freitag DF, Pennells L, Peters SA, Hart CL, Håheim LL, Gillum RF, .. gregation and adhesion. Magnesium modulates surface expression of glycopro- Nordestgaard BG, Psaty BM, Yeap BB, Knuiman MW, Nietert PJ, Kauhanen J, .. teins on platelets in vitro and ex vivo. Thromb Haemost 1994;72:912–918. Salonen JT, Kuller LH, Simons LA, van der Schouw YT, Barrett-Connor E, .. Selmer R, Crespo CJ, Rodriguez B, Verschuren WMM, Salomaa V, Svärdsudd K, .. 21. Hernández Vera R, Vilahur G, Ferrer-Lorente R, Pe~ na E, Badimon L. Platelets .. derived from the bone marrow of diabetic animals show dysregulated endo- van der Harst P, Björkelund C, Wilhelmsen L, Wallace RB, Brenner H, .. plasmic reticulum stress proteins that contribute to increased thrombosis. Amouyel P, Barr ELM, Iso H, Onat A, Trevisan M, D’Agostino RB, Cooper C, .. Arterioscler Thromb Vasc Biol 2012;32:2141–2148. Kavousi M, Welin L, Roussel R, Hu FB, Sato S, Davidson KW, Howard BV, .. 22. Wang Y, Beck W, Deppisch R, Marshall SM, Hoenich NA, Thompson MG. Leening MJG, Leening M, Rosengren A, Dörr M, Deeg DJH, Kiechl S, .. Advanced glycation end products elicit externalization of phosphatidylserine in Stehouwer CDA, Nissinen A, Giampaoli S, Donfrancesco C, Kromhout D, .. a subpopulation of platelets via 5-HT2A/2C receptors. Am J Physiol Cell Physiol Price JF, Peters A, Meade TW, Casiglia E, Lawlor DA, Gallacher J, Nagel D, .. Franco OH, Assmann G, Dagenais GR, Jukema JW, Sundström J, Woodward M, .. 2007;293:C328–C336. .. 23. Rocca B, Santilli F, Pitocco D, Mucci L, Petrucci G, Vitacolonna E, Lattanzio S, Brunner EJ, Khaw K-T, Wareham NJ, Whitsel EA, Njølstad I, Hedblad B, .. Mattoscio D, Zaccardi F, Liani R, Vazzana N, Del Ponte A, Ferrante E, Martini F, Wassertheil-Smoller S, Engström G, Rosamond WD, Selvin E, Sattar N, .. Cardillo C, Morosetti R, Mirabella M, Ghirlanda G, Davi G, Patrono C. The re- Thompson SG, Danesh J. Association of cardiometabolic multimorbidity with .. covery of platelet cyclooxygenase activity explains interindividual variability in mortality. JAMA 2015;314:52–60. .. responsiveness to low-dose aspirin in patients with and without diabetes. J 2. Emerging Risk Factors Collaboration; Sarwar N, Gao P, Seshasai SR, Gobin R, .. Thromb Haemost 2012;10:1220–1230. Kaptoge S, Di Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M, .. Stehouwer CD, Lewington S, Pennells L, Thompson A, Sattar N, White IR, Ray .. 24. Vilahur G, Ben-Aicha S, Badimon L. New insights into the role of adipose tissue .. in thrombosis. Cardiovasc Res 2017;113:1046–1054. KK, Danesh J. Diabetes mellitus, fasting blood glucose concentration, and risk of .. 25. Ferreiro JL, Gomez-Hospital JA, Angiolillo DJ. Platelet abnormalities in diabetes vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet .. mellitus. Diab Vasc Dis Res 2010;7:251–259. 2010;375:2215–2222. .. 26. Alzahrani SH, Ajjan RA. Coagulation and fibrinolysis in diabetes. Diab Vasc Dis 3. Cosentino F, Ceriello A, Baeres FMM, Fioretto P, Garber A, Stough WG, .. Res 2010;7:260–273. George JT, Grant PJ, Khunti K, Langkilde AM, Plutzky J, Ryden L, Scheen A, .. 27. Kim HK, Kim JE, Park SH, Kim YI, Nam-Goong IS, Kim ES. High coagulation fac- Standl E, Tuomilehto J, Zannad F. Addressing cardiovascular risk in type 2 dia- .. tor levels and low protein C levels contribute to enhanced thrombin generation betes mellitus: a report from the European Society of Cardiology .. .. in patients with diabetes who do not have macrovascular complications. J Cardiovascular Roundtable. Eur Heart J 2019;40:2907–2919. .. Diabetes Complications 2014;28:365–369. 4. Carrizzo A, Izzo C, Oliveti M, Alfano A, Virtuoso N, Capunzo M, Di Pietro P, .. 28. Ajjan RA, Gamlen T, Standeven KF, Mughal S, Hess K, Smith KA, Dunn EJ, Calabrese M, De Simone E, Sciarretta S, Frati G, Migliarino S, Damato A, .. Anwar MM, Rabbani N, Thornalley PJ, Philippou H, Grant PJ. Diabetes is associ- Ambrosio M, De Caro F, Vecchione C. The main determinants of diabetes mel- .. ated with posttranslational modifications in plasminogen resulting in reduced litus vascular complications: endothelial dysfunction and platelet hyperaggrega- .. plasmin generation and enzyme-specific activity. Blood 2013;122:134–142. tion. Int J Mol Sci 2018;19:2968. .. 29. Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, 5. Rivas Rios JR, Franchi F, Rollini F, Angiolillo DJ. Diabetes and antiplatelet ther- .. .. Brownlee M. Hyperglycemia-induced mitochondrial superoxide overproduction apy: from bench to bedside. Cardiovasc Diagn Ther 2018;8:594–609. .. activates the hexosamine pathway and induces plasminogen activator inhibitor- 6. Kearney K, Tomlinson D, Smith K, Ajjan R. Hypofibrinolysis in diabetes: a thera- .. 1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci USA 2000;97: peutic target for the reduction of cardiovascular risk. Cardiovasc Diabetol 2017; .. 12222–12226. 16:34. .. 30. James S, Angiolillo DJ, Cornel JH, Erlinge D, Husted S, Kontny F, Maya J, 7. Mi Y, Yan S, Lu Y, Liang Y, Li C. Venous thromboembolism has the same risk .. Nicolau JC, Spinar J, Storey RF, Stevens SR, Wallentin L; PLATO Study Group. factors as atherosclerosis: a PRISMA-compliant systemic review and meta-ana- .. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and dia- lysis. Medicine (Baltimore) 2016;95:e4495. .. 8. Pretorius E. Platelets as potent signaling entities in type 2 diabetes mellitus. .. betes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) .. trial. Eur Heart J 2010;31:3006–3016. Trends Endocrinol Metab 2019;30:532–545. .. 31. Ducrocq G, Wallace JS, Baron G, Ravaud P, Alberts MJ, Wilson PWF, Ohman 9. Soma P, Swanepoel AC, Du Plooy JN, Mqoco T, Pretorius E. Flow cytometric .. EM, Brennan DM, D’Agostino RB, Bhatt DL, Steg PG; on behalf of the REACH analysis of platelets type 2 diabetes mellitus reveals ‘angry’ platelets. Cardiovasc .. Investigators. Risk score to predict serious bleeding in stable outpatients with Diabetol 2016;15:52. .. or at risk of atherothrombosis. Eur Heart J 2010;31:1257–1265. 10. Ghoshal K, Bhattacharyya M. Overview of platelet physiology: its hemostatic .. 32. Lemesle G, Meurice T, Tricot O, Lamblin N, Bauters C. Association of diabetic and nonhemostatic role in disease pathogenesis. ScientificWorldJournal 2014; .. 2014:781857. .. status and glycemic control with ischemic and bleeding outcomes in patients .. with stable coronary artery disease: the 5-Year CORONOR Registry. J Am 11. Patrono C, Rocca B. Measurement of thromboxane biosynthesis in health and .. Heart Assoc 2018;7:e008354. disease. Front Pharmacol 2019;10:1244. .. 33. Goel N, Jain D, Haddad DB, Shanbhogue D. Anticoagulation in patients with 12. Watala C, Boncer M, Gola nski J, Koziołkiewicz W, Trojanowski Z, Walkowiak .. end-stage renal disease and atrial fibrillation: confusion, concerns and conse- B. Platelet membrane lipid fluidity and intraplatelet calcium mobilization in type .. quences. J Stroke 2020;22:306–316. 2 diabetes mellitus. Eur J Haematol 2009;61:319–326. .. 34. Nogami K, Muraki I, Imano H, Iso H. Risk of disseminated intravascular coagula- 13. Santilli F, Simeone P, Liani R, Davi G. Platelets and diabetes mellitus. .. Prostaglandins Other Lipid Mediat 2015;120:28–39. .. tion in patients with type 2 diabetes mellitus: retrospective cohort study. BMJ .. Open 2017;7:e013894. 14. Audoly LP, Rocca B, Fabre JE, Koller BH, Thomas D, Loeb AL, Coffman TM, .. 35. Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C. Low-dose aspirin for FitzGerald GA. Cardiovascular responses to the isoprostanes iPF(2alpha)-III and .. the prevention of atherothrombosis. N Engl J Med 2005;353:2373–2383. iPE(2)-III are mediated via the thromboxane A(2) receptor in vivo. Circulation .. 36. Capodanno D, Angiolillo DJ. Aspirin for primary cardiovascular risk prevention 2000;101:2833–2840. .. and beyond in diabetes mellitus. Circulation 2016;134:1579–1594. 15. Hunter RW, Hers I. Insulin/IGF-1 hybrid receptor expression on human plate- .. 37. Angiolillo DJ, Ueno M, Goto S. Basic principles of platelet biology and clinical lets: consequences for the effect of insulin on platelet function. J Thromb .. implications. Circ J 2010;74:597–607. Haemost 2009;7:2123–2130. .. .. 38. Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. 16. Westein E, Hoefer T, Calkin AC. Thrombosis in diabetes: a shear flow effect? .. Nat Rev Cardiol 2015;12:30–47. Clin Sci (Lond) 2017;131:1245–1260. .. 39. Andreotti F, Testa L, Biondi-Zoccai GG, Crea F. Aspirin plus warfarin compared 17. Vinik AI, Erbas T, Park TS, Nolan R, Pittenger GL. Platelet dysfunction in type 2 .. to aspirin alone after acute coronary syndromes: an updated and comprehen- diabetes. Diabetes Care 2001;24:1476–1485. .. sive meta-analysis of 25,307 patients. Eur Heart J 2006;27:519–526. 18. Fejes Z, Poliska S, Czimmerer Z, Kaplar M, Penyige A, Gal Szabo G, Beke .. 40. Angiolillo DJ, Capodanno D, Goto S. Platelet thrombin receptor antagonism Debreceni I, Kunapuli SP, Kappelmayer J, Nagy BJ. Hyperglycaemia suppresses .. and atherothrombosis. Eur Heart J 2010;31:17–28. Antithrombotic therapy in diabetes 2255 41. Angiolillo DJ, Ferreiro JL. Antiplatelet and anticoagulant therapy for athero- .. segment elevation: task Force for the Management of Acute Coronary .. thrombotic disease: the role of current and emerging agents. Am J Cardiovasc .. Syndromes in Patients Presenting without Persistent ST-Segment Elevation of Drugs 2013;13:233–250. .. the European Society of Cardiology (ESC). Eur Heart J 2016;37:267–315. 42. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, .. 56. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A. .. Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Aspirin in the primary and secondary prevention of vascular disease: collabora- .. Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, tive meta-analysis of individual participant data from randomised trials. Lancet .. Widimsky P; ESC Scientific Document Group. 2017 ESC Guidelines for the 2009;373:1849–1860. .. management of acute myocardial infarction in patients presenting with ST- .. 43. Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, Doi N, Jinnouchi .. segment elevation: the Task Force for the management of acute myocardial in- H, Sugiyama S, Saito Y; Japanese Primary Prevention of Atherosclerosis With .. farction in patients presenting with ST-segment elevation of the European Aspirin for Diabetes (JPAD) Trial Investigators. Low-dose aspirin for primary .. Society of Cardiology (ESC). Eur Heart J 2018;39:119–177. prevention of atherosclerotic events in patients with type 2 diabetes: a random- .. 57. Alexopoulos D, Vogiatzi C, Stavrou K, Vlassopoulou N, Perperis A, Pentara I, ized controlled trial. JAMA 2008;300:2134–2141. .. Xanthopoulou I. Diabetes mellitus and platelet reactivity in patients under pra- 44. Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R, Lee R, .. sugrel or ticagrelor treatment: an observational study. Cardiovasc Diabetol 2015; Bancroft J, MacEwan S, Shepherd J, Macfarlane P, Morris A, Jung R, Kelly C, .. 14:68. .. Connacher A, Peden N, Jamieson A, Matthews D, Leese G, McKnight J, O’Brien .. 58. Thomas MR, Angiolillo DJ, Bonaca MP, Ajjan RA, Judge HM, Rollini F, Franchi F, I, Semple C, Petrie J, Gordon D, Pringle S, MacWalter R; Prevention of .. Ahsan AJ, Bhatt DL, Kuder JF, Steg PG, Cohen M, Muthusamy R, Sabatine MS, Progression of Arterial Disease and Diabetes Study Group; Diabetes Registry .. Storey RF. Consistent platelet inhibition with ticagrelor 60 mg twice-daily fol- Group; Royal College of Physicians Edinburgh. The prevention of progression .. lowing myocardial infarction regardless of diabetes status. Thromb Haemost of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo .. 2017;117:940–947. controlled trial of aspirin and antioxidants in patients with diabetes and asymp- .. 59. Capodanno D, Patel A, Dharmashankar K, Ferreiro JL, Ueno M, Kodali M, tomatic peripheral arterial disease. BMJ 2008;337:a1840. .. Tomasello SD, Capranzano P, Seecheran N, Darlington A, Tello-Montoliu A, .. 45. Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, Murphy K, .. Desai B, Bass TA, Angiolillo DJ. Pharmacodynamic effects of different aspirin Aung T, Haynes R, Cox J, Murawska A, Young A, Lay M, Chen F, Sammons E, .. dosing regimens in type 2 diabetes mellitus patients with coronary artery dis- Waters E, Adler A, Bodansky J, Farmer A, McPherson R, Neil A, Simpson D, .. ease. Circ Cardiovasc Interv 2011;4:180–187. Peto R, Baigent C, Collins R, Parish S, Armitage J; ASCEND Study Collaborative .. 60. Spectre G, Arnetz L, Ostenson CG, Brismar K, Li N, Hjemdahl P. Twice daily Group. Effects of aspirin for primary prevention in persons with diabetes melli- .. dosing of aspirin improves platelet inhibition in whole blood in patients with tus. N Engl J Med 2018;379:1529–1539. .. type 2 diabetes mellitus and micro- or macrovascular complications. Thromb 46. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, .. Haemost 2011;106:491–499. .. Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, .. 61. Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Eikelboom JW, Fox KA, Granger Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. .. CB, Jolly S, Joyner CD, Rupprecht HJ, Widimsky P, Afzal R, Pogue J, Yusuf S; Standardized bleeding definitions for cardiovascular clinical trials: a consensus .. CURRENT-OASIS 7 Investigators. Dose comparisons of clopidogrel and aspirin report from the Bleeding Academic Research Consortium. Circulation 2011;123: .. in acute coronary syndromes. N Engl J Med 2010;363:930–942. 2736–2747. .. 62. Johnston A, Jones WS, Hernandez AF. The ADAPTABLE trial and aspirin dosing 47. Steg PG, Bhatt DL, Simon T, Fox K, Mehta SR, Harrington RA, Held C, .. in secondary prevention for patients with coronary artery disease. Curr Cardiol Andersson M, Himmelmann A, Ridderstråle W, Leonsson-Zachrisson M, Liu Y, .. Rep 2016;18:81. Opolski G, Zateyshchikov D, Ge J, Nicolau JC, Corbalán R, Cornel JH, .. 63. Angiolillo DJ, Bhatt DL, Lanza F, Cryer B, Dong JF, Jeske W, Zimmerman RR, .. Widimsky P, Leiter LA; THEMIS Steering Committee and Investigators. .. von Chong E, Prats J, Deliargyris EN, Marathi U. Pharmacokinetic/pharmacody- Ticagrelor in patients with stable coronary disease and diabetes. N Engl J Med .. namic assessment of a novel, pharmaceutical lipid-aspirin complex: results of a 2019;381:1309–1320. .. randomized, crossover, bioequivalence study. J Thromb Thrombolysis 2019;48: 48. Bhatt DL, Bonaca MP, Bansilal S, Angiolillo DJ, Cohen M, Storey RF, Im K, .. 554–562. Murphy SA, Held P, Braunwald E, Sabatine MS, Steg PG. Reduction in ischemic .. 64. Bhatt DL, Grosser T, Dong J-F, Logan D, Jeske W, Angiolillo DJ, Frelinger AL, events with ticagrelor in diabetic patients with prior myocardial infarction in .. Lei L, Liang J, Moore JE, Cryer B, Marathi U. Enteric coating and aspirin nonres- PEGASUS-TIMI 54. J Am Coll Cardiol 2016;67:2732–2740. .. ponsiveness in patients with type 2 diabetes mellitus. J Am Coll Cardiol 2017;69: .. 49. Vranckx P, White HD, Huang Z, Mahaffey KW, Armstrong PW, Van de Werf F, .. 603–612. Moliterno DJ, Wallentin L, Held C, Aylward PE, Cornel JH, Bode C, Huber K, .. 65. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow Nicolau JC, Ruzyllo W, Harrington RA, Tricoci P. Validation of BARC bleeding .. J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, criteria in patients with acute coronary syndromes: the TRACER trial. J Am Coll .. Storey RF, Harrington RA; PLATO Investigators. Ticagrelor versus clopidogrel Cardiol 2016;67:2135–2144. .. in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–1057. 50. Seidu S, Kunutsor SK, Sesso HD, Gaziano JM, Buring JE, Roncaglioni MC, Khunti .. 66. Wiviott SD, Braunwald E, Angiolillo DJ, Meisel S, Dalby AJ, Verheugt FW, K. Aspirin has potential benefits for primary prevention of cardiovascular out- .. Goodman SG, Corbalan R, Purdy DA, Murphy SA, McCabe CH, Antman EM; .. comes in diabetes: updated literature-based and individual participant data .. TRITON-TIMI 38 Investigators. Greater clinical benefit of more intensive oral meta-analyses of randomized controlled trials. Cardiovasc Diabetol 2019;18:70. .. antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial 51. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, .. to assess improvement in therapeutic outcomes by optimizing platelet inhib- Filippatos G, Grobbee DE, Hansen TB, Huikuri HV, Johansson I, Juni P, Lettino .. ition with prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation 2008; M, Marx N, Mellbin LG, Ostgren CJ, Rocca B, Roffi M, Sattar N, Seferovic PM, .. 118:1626–1636. Sousa-Uva M, Valensi P, Wheeler DC; ESC Scientific Document Group. 2019 .. 67. Angiolillo DJ, Jakubowski JA, Ferreiro JL, Tello-Montoliu A, Rollini F, Franchi F, ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases devel- .. Ueno M, Darlington A, Desai B, Moser BA, Sugidachi A, Guzman LA, Bass TA. .. oped in collaboration with the EASD. Eur Heart J 2020;41:255–323. .. Impaired responsiveness to the platelet P2Y12 receptor antagonist clopidogrel 52. American Diabetes Association. 10. Cardiovascular Disease and Risk .. in patients with type 2 diabetes and coronary artery disease. J Am Coll Cardiol Management: standards of Medical Care in Diabetes-2019. Diabetes Care 2019; .. 2014;64:1005–1014. 42(Suppl 1):S103–S123. .. 68. Franchi F, James SK, Ghukasyan LT, Budaj AJ, Cornel JH, Katus HA, Keltai M, 53. Bibbins-Domingo K; U.S. Preventive Services Task Force. Aspirin use for the .. Kontny F, Lewis BS, Storey RF, Himmelmann A, Wallentin L, Angiolillo DJ; primary prevention of cardiovascular disease and colorectal cancer: U.S. .. PLATO Investigators. Impact of diabetes mellitus and chronic kidney disease on Preventive Services Task Force recommendation statement. Ann Intern Med .. cardiovascular outcomes and platelet P2Y12 receptor antagonist effects in 2016;164:836–845. .. patients with acute coronary syndromes: insights from the PLATO trial. J Am .. 54. Bell AD, Roussin A, Cartier R, Chan WS, Douketis JD, Gupta A, Kraw ME, .. Heart Assoc 2019;8:e011139. Lindsay TF, Love MP, Pannu N, Rabasa-Lhoret R, Shuaib A, Teal P, Theroux P, .. 69. Schupke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, Wohrle J, Turpie AG, Welsh RC, Tanguay JF. The use of antiplatelet therapy in the out- .. Richardt G, Liebetrau C, Witzenbichler B, Antoniucci D, Akin I, Bott-Flugel L, patient setting: Canadian Cardiovascular Society Guidelines Executive .. Fischer M, Landmesser U, Katus HA, Sibbing D, Seyfarth M, Janisch M, Summary. Can J Cardiol 2011;27:208–221. .. Boncompagni D, Hilz R, Rottbauer W, Okrojek R, Mollmann H, Hochholzer 55. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, .. W, Migliorini A, Cassese S, Mollo P, Xhepa E, Kufner S, Strehle A, Leggewie S, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, .. Allali A, Ndrepepa G, Schuhlen H, Angiolillo DJ, Hamm CW, Hapfelmeier A, .. Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S; .. Tolg R, Trenk D, Schunkert H, Laugwitz KL, Kastrati A; ISAR-REACT 5 Trial ESC Scientific Document Group. 2015 ESC Guidelines for the management of .. Investigators. Ticagrelor or prasugrel in patients with acute coronary syn- acute coronary syndromes in patients presenting without persistent ST- . dromes. N Engl J Med 2019;381:1524–1534. 2256 R.A. Ajjan et al. 70. Ndrepepa G, Kastrati A, Menichelli M, Neumann FJ, Wohrle J, Bernlochner I, .. intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized .. Richardt G, Witzenbichler B, Sibbing D, Gewalt S, Angiolillo DJ, Hamm CW, .. trial. JAMA 2006;295:1531–1538. Hapfelmeier A, Trenk D, Laugwitz KL, Schunkert H, Schupke S, Mayer K. .. 82. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, Ticagrelor or prasugrel in patients with acute coronary syndromes and diabetes .. Byrne RA, Collet JP, Falk V, Head SJ, Juni P, Kastrati A, Koller A, Kristensen SD, mellitus. JACC Cardiovasc Interv 2020;13:2238–2247. .. Niebauer J, Richter DJ, Seferovic PM, Sibbing D, Stefanini GG, Windecker S, 71. Cayla G, Cuisset T, Silvain J, Leclercq F, Manzo-Silberman S, Saint-Etienne C, .. Yadav R, Zembala MO; ESC Scientific Document Group. 2018 ESC/EACTS Delarche N, Bellemain-Appaix A, Range G, El Mahmoud R, Carrie D, Belle L, .. Guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. Souteyrand G, Aubry P, Sabouret P, Du Fretay XH, Beygui F, Bonnet JL, Lattuca .. 83. Zwart B, Yazdani M, Ow KW, Richardson JD, Iqbal J, Gunn JP, Storey RF. Use .. B, Pouillot C, Varenne O, Boueri Z, Van Belle E, Henry P, Motreff P, Elhadad S, .. of glycoprotein IIb/IIIa antagonists to prevent stent thrombosis in morphine- Salem JE, Abtan J, Rousseau H, Collet JP, Vicaut E, Montalescot G; .. treated patients with ST-elevation myocardial infarction. Platelets 2020;31: ANTARCTIC Investigators. Platelet function monitoring to adjust antiplatelet .. 174–178. therapy in elderly patients stented for an acute coronary syndrome .. 84. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled super- .. Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, iority trial. Lancet 2016;388:2015–2022. .. Schneider D, Sun X, Verheugt FW, Gibson CM; ATLAS ACS 2-TIMI 51 72. Hein R, Gross L, Aradi D, Rieber J, Hadamitzky M, Merkely B, Huczek Z, Ince .. Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. .. H, Hummel A, Baylacher M, Massberg S, Trenk D, Sibbing D. Diabetes and out- .. N Engl J Med 2012;366:9–19. comes following guided de-escalation of antiplatelet treatment in acute coron- .. 85. Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, ary syndrome patients undergoing percutaneous coronary intervention: a pre- .. Prescott E, Storey RF, Deaton C, Cuisset T, Agewall S, Dickstein K, Edvardsen specified analysis from the randomised TROPICAL-ACS trial. EuroIntervention .. T, Escaned J, Gersh BJ, Svitil P, Gilard M, Hasdai D, Hatala R, Mahfoud F, Masip 2019;15:e513–e521. .. J, Muneretto C, Valgimigli M, Achenbach S, Bax JJ; ESC Scientific Document 73. Mehran R, Baber U, Sharma SK, Cohen DJ, Angiolillo DJ, Briguori C, Cha JY, .. Group. 2019 ESC Guidelines for the diagnosis and management of chronic cor- Collier T, Dangas G, Dudek D, Dzavik V, Escaned J, Gil R, Gurbel P, Hamm .. onary syndromes. Eur Heart J 2020;41:407–477. .. CW, Henry T, Huber K, Kastrati A, Kaul U, Kornowski R, Krucoff M, Kunadian .. 86. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus V, Marx SO, Mehta SR, Moliterno D, Ohman EM, Oldroyd K, Sardella G, .. aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348: Sartori S, Shlofmitz R, Steg PG, Weisz G, Witzenbichler B, Han YL, Pocock S, .. 1329–1339. Gibson CM. Ticagrelor with or without aspirin in high-risk patients after PCI. N .. 87. Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Amplified Engl J Med 2019;381:2032–2042. .. benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J 74. Angiolillo DJ, Baber U, Sartori S, Briguori C, Dangas G, Cohen DJ, Mehta SR, .. Cardiol 2002;90:625–628. Gibson CM, Chandiramani R, Huber K, Kornowski R, Weisz G, Kunadian V, .. 88. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, .. Oldroyd KG, Ya-Ling H, Kaul U, Witzenbichler B, Dudek D, Sardella G, .. Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR Jr, Krucoff MW, Escaned J, Sharma S, Shlofmitz RA, Collier T, Pocock S, Mehran R. Ticagrelor .. Hermiller J, Dauerman HL, Simon DI, Kandzari DE, Garratt KN, Lee DP, Pow with or without aspirin in high-risk patients with diabetes mellitus undergoing .. TK, Ver Lee P, Rinaldi MJ, Massaro JM; DAPT Study Investigators. Twelve or 30 percutaneous coronary intervention. J Am Coll Cardiol 2020;75:2403–2413. .. months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 75. Vranckx P, Valgimigli M, Juni P, Hamm C, Steg PG, Heg D, van Es GA, .. 371:2155–2166. McFadden EP, Onuma Y, van Meijeren C, Chichareon P, Benit E, Mollmann H, .. 89. Meredith IT, Tanguay JF, Kereiakes DJ, Cutlip DE, Yeh RW, Garratt KN, Lee Janssens L, Ferrario M, Moschovitis A, Zurakowski A, Dominici M, Van Geuns .. DP, Steg PG, Weaver WD, Holmes DR Jr, Brindis RG, Trebacz J, Massaro JM, RJ, Huber K, Slagboom T, Serruys PW, Windecker S; GLOBAL LEADERS .. Hsieh WH, Mauri L; DAPT Study Investigators. Diabetes mellitus and preven- .. Investigators. Ticagrelor plus aspirin for 1 month, followed by ticagrelor mono- .. tion of late myocardial infarction after coronary stenting in the randomized dual therapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, .. antiplatelet therapy study. Circulation 2016;133:1772–1782. followed by aspirin monotherapy for 12 months after implantation of a drug- .. 90. Gargiulo G, Windecker S, da Costa BR, Feres F, Hong MK, Gilard M, Kim HS, eluting stent: a multicentre, open-label, randomised superiority trial. Lancet .. Colombo A, Bhatt DL, Kim BK, Morice MC, Park KW, Chieffo A, Palmerini T, 2018;392:940–949. .. Stone GW, Valgimigli M. Short term versus long term dual antiplatelet therapy 76. Chichareon P, Modolo R, Kogame N, Takahashi K, Chang C-C, Tomaniak M, .. after implantation of drug eluting stent in patients with or without diabetes: sys- Botelho R, Eeckhout E, Hofma S, Trendafilova-Lazarova D, K} oszegi Z, I~niguez .. tematic review and meta-analysis of individual participant data from randomised .. A, Wykrzykowska JJ, Piek JJ, Garg S, Hamm C, Steg PG, Jüni P, Vranckx P, .. trials. BMJ 2016;355:i5483. Valgimigli M, Windecker S, Onuma Y, Serruys PW. Association of diabetes with .. 91. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, outcomes in patients undergoing contemporary percutaneous coronary inter- .. Bansilal S, Fish MP, Im K, Bengtsson O, Oude Ophuis T, Budaj A, Theroux P, vention: pre-specified subgroup analysis from the randomized GLOBAL .. Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, Murphy SA, Wiviott LEADERS study. Atherosclerosis 2020;295:45–53. .. SD, Held P, Braunwald E, Sabatine MS; PEGASUS-TIMI 54 Steering Committee 77. Gao C, Tomaniak M, Takahashi K, Kawashima H, Wang R, Hara H, Ono M, .. and Investigators. Long-term use of ticagrelor in patients with prior myocardial Montalescot G, Garg S, Haude M, Slagboom T, Vranckx P, Valgimigli M, .. infarction. N Engl J Med 2015;372:1791–1800. .. Windecker S, van Geuns RJ, Hamm C, Steg PG, Onuma Y, Angiolillo DJ, .. 92. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, Serruys PW. Ticagrelor monotherapy in patients with concomitant diabetes .. Diaz R, Alings M, Lonn EM, Anand SS, Widimsky P, Hori M, Avezum A, Piegas mellitus and chronic kidney disease: a post hoc analysis of the GLOBAL .. LS, Branch KRH, Probstfield J, Bhatt DL, Zhu J, Liang Y, Maggioni AP, Lopez- LEADERS trial. Cardiovasc Diabetol 2020;19:179. .. Jaramillo P, O’Donnell M, Kakkar AK, Fox KAA, Parkhomenko AN, Ertl G, 78. Malik AH, Yandrapalli S, Shetty SS, Aronow WS, Cooper HA, Panza JA. Meta- .. Störk S, Keltai M, Ryden L, Pogosova N, Dans AL, Lanas F, Commerford PJ, analysis of dual antiplatelet therapy versus monotherapy with P2Y12 inhibitors .. Torp-Pedersen C, Guzik TJ, Verhamme PB, Vinereanu D, Kim J-H, Tonkin AM, in patients after percutaneous coronary intervention. Am J Cardiol 2020;127: .. Lewis BS, Felix C, Yusoff K, Steg PG, Metsarinne KP, Cook Bruns N, Misselwitz .. 25–29. .. F, Chen E, Leong D, Yusuf S; COMPASS Investigators. Rivaroxaban with or 79. Capodanno D, Morice MC, Angiolillo DJ, Bhatt DL, Byrne RA, Colleran R, .. without aspirin in stable cardiovascular disease. N Engl J Med 2017;377: Cuisset T, Cutlip D, Eerdmans P, Eikelboom J, Farb A, Gibson CM, Gregson J, .. 1319–1330. Haude M, James SK, Kim HS, Kimura T, Konishi A, Leon MB, Magee PFA, .. 93. Sumaya W, Geisler T, Kristensen SD, Storey RF. Dual antiplatelet or dual Mitsutake Y, Mylotte D, Pocock SJ, Rao SV, Spitzer E, Stockbridge N, Valgimigli .. antithrombotic therapy for secondary prevention in high-risk patients with sta- M, Varenne O, Windhovel U, Krucoff MW, Urban P, Mehran R. Trial design .. ble coronary artery disease? Thromb Haemost 2019;119:1583–1589. principles for patients at high bleeding risk undergoing PCI: JACC Scientific .. 94. Anand SS, Eikelboom JW, Dyal L, Bosch J, Neumann C, Widimsky P, Avezum Expert Panel. J Am Coll Cardiol 2020;76:1468–1483. .. AA, Probstfield J, Cook Bruns N, Fox KAA, Bhatt DL, Connolly SJ, Yusuf S; .. 80. Roffi M, Chew DP, Mukherjee D, Bhatt DL, White JA, Heeschen C, Hamm .. COMPASS Trial Investigators. Rivaroxaban plus aspirin versus aspirin in relation CW, Moliterno DJ, Califf RM, White HD, Kleiman NS, Theroux P, Topol EJ. .. to vascular risk in the COMPASS trial. J Am Coll Cardiol 2019;73:3271–3280. Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with .. 95. Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ, Fish MP, Fox KA, non-ST-segment-elevation acute coronary syndromes. Circulation 2001;104: .. Lipka LJ, Liu X, Nicolau JC, Ophuis AJ, Paolasso E, Scirica BM, Spinar J, Theroux 2767–2771. .. P, Wiviott SD, Strony J, Murphy SA; TRA 2P-TIMI 50 Steering Committee and 81. Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein H, Graf I, .. Investigators. Vorapaxar in the secondary prevention of atherothrombotic Ibrahim M, Pache J, Seyfarth M, Schuhlen H, Dirschinger J, Berger PB, Schomig .. events. N Engl J Med 2012;366:1404–1413. .. A; Intracoronary Stenting and Antithrombotic: Regimen Rapid Early Action for .. 96. Scirica BM, Bonaca MP, Braunwald E, De Ferrari GM, Isaza D, Lewis BS, Coronary Treatment 2 (ISAR-REACT 2) Trial Investigators. Abciximab in .. Mehrhof F, Merlini PA, Murphy SA, Sabatine MS, Tendera M, Van de Werf F, patients with acute coronary syndromes undergoing percutaneous coronary . Wilcox R, Morrow DA; TRA 2 P-TIMI 50 Steering Committee and Antithrombotic therapy in diabetes 2257 Investigators. Vorapaxar for secondary prevention of thrombotic events for .. Angiolillo DJ. Management of antithrombotic therapy in atrial fibrillation .. patients with previous myocardial infarction: a prespecified subgroup analysis of .. patients undergoing PCI: JACC state-of-the-art review. J Am Coll Cardiol 2019; the TRA 2 degrees P-TIMI 50 trial. Lancet 2012;380:1317–1324. .. 74:83–99. 97. Cavender MA, Scirica BM, Bonaca MP, Angiolillo DJ, Dalby AJ, Dellborg M, .. 116. Boriani G, Fauchier L, Aguinaga L, Beattie JM, Blomstrom Lundqvist C, Cohen Morais J, Murphy SA, Ophuis TO, Tendera M, Braunwald E, Morrow DA. .. A, Dan G-A, Genovesi S, Israel C, Joung B, Kalarus Z, Lampert R, Malavasi VL, Vorapaxar in patients with diabetes mellitus and previous myocardial infarction: .. Mansourati J, Mont L, Potpara T, Thornton A, Lip GYH, Gorenek B, Marin F, findings from the Thrombin Receptor Antagonist in Secondary Prevention of .. Dagres N, Ozcan EE, Lenarczyk R, Crijns HJ, Guo Y, Proietti M, Sticherling C, Atherothrombotic Ischemic Events-TIMI 50 trial. Circulation 2015;131: .. Huang D, Daubert JP, Pokorney SD, Cabrera Ortega M, Chin A; ESC Scientific .. 1047–1053. .. Document Group. European Heart Rhythm Association (EHRA) consensus 98. Storey RF. The long journey of individualizing antiplatelet therapy after acute .. document on management of arrhythmias and cardiac electronic devices in the coronary syndromes. Eur Heart J 2020;41:3546–3548. .. critically ill and post-surgery patient, endorsed by Heart Rhythm Society (HRS), 99. Pallisgaard JL, Schjerning AM, Lindhardt TB, Procida K, Hansen ML, Torp- .. Asia Pacific Heart Rhythm Society (APHRS), Cardiac Arrhythmia Society of Pedersen C, Gislason GH. Risk of atrial fibrillation in diabetes mellitus: a nation- .. Southern Africa (CASSA), and Latin American Heart Rhythm Society (LAHRS). wide cohort study. Eur J Prev Cardiol 2016;23:621–627. .. Europace 2019;21:7–8. 100. Overvad TF, Skjoth F, Lip GY, Lane DA, Albertsen IE, Rasmussen LH, Larsen .. 117. Lip GYH, Collet J-P, Haude M, Byrne R, Chung EH, Fauchier L, Halvorsen S, .. TB. Duration of diabetes mellitus and risk of thromboembolism and bleeding in .. Lau D, Lopez-Cabanillas N, Lettino M, Marin F, Obel I, Rubboli A, Storey RF, atrial fibrillation: nationwide cohort study. Stroke 2015;46:2168–2174. .. Valgimigli M, Huber K, Potpara T, Blomström Lundqvist C, Crijns H, Steffel J, 101. Dublin S, Glazer NL, Smith NL, Psaty BM, Lumley T, Wiggins KL, Page RL, .. Heidbüchel H, Stankovic G, Airaksinen J, Ten Berg JM, Capodanno D, James S, Heckbert SR. Diabetes mellitus, glycemic control, and risk of atrial fibrillation. J .. Bueno H, Morais J, Sibbing D, Rocca B, Hsieh M-H, Akoum N, Lockwood DJ, Gen Intern Med 2010;25:853–858. .. Gomez Flores JR, Jardine R; ESC Scientific Document Group. 2018 Joint 102. Wang A, Green JB, Halperin JL, Piccini JP Sr. Atrial fibrillation and diabetes mel- .. European consensus document on the management of antithrombotic therapy litus: JACC review topic of the week. J Am Coll Cardiol 2019;74:1107–1115. .. in atrial fibrillation patients presenting with acute coronary syndrome and/or .. 103. Plitt A, McGuire DK, Giugliano RP. Atrial fibrillation, type 2 diabetes, and non- .. undergoing percutaneous cardiovascular interventions: a joint consensus docu- vitamin K antagonist oral anticoagulants: a review. JAMA Cardiol 2017;2:442–448. .. ment of the European Heart Rhythm Association (EHRA), European Society of 104. Huxley RR, Alonso A, Lopez FL, Filion KB, Agarwal SK, Loehr LR, Soliman EZ, .. Cardiology Working Group on Thrombosis, European Association of Pankow JS, Selvin E. Type 2 diabetes, glucose homeostasis and incident atrial .. Percutaneous Cardiovascular Interventions (EAPCI), and European Association fibrillation: the Atherosclerosis Risk in Communities study. Heart 2012;98: .. of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS), 133–138. .. Asia-Pacific Heart Rhythm Society (APHRS), Latin America Heart Rhythm 105. Anselmino M, Matta M, D’Ascenzo F, Pappone C, Santinelli V, Bunch TJ, .. Society (LAHRS), and Cardiac Arrhythmia Society of Southern Africa (CASSA). .. Neumann T, Schilling RJ, Hunter RJ, Noelker G, Fiala M, Frontera A, Thomas G, .. Europace 2019;21:192–193. Katritsis D, Jais P, Weerasooriya R, Kalman JM, Gaita F. Catheter ablation of .. 118. Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, atrial fibrillation in patients with diabetes mellitus: a systematic review and .. Norman PE, Sampson UK, Williams LJ, Mensah GA, Criqui MH. Comparison of meta-analysis. Europace 2015;17:1518–1525. .. global estimates of prevalence and risk factors for peripheral artery disease in 106. Fatemi O, Yuriditsky E, Tsioufis C, Tsachris D, Morgan T, Basile J, Bigger T, .. 2000 and 2010: a systematic review and analysis. Lancet 2013;382:1329–1340. Cushman W, Goff D, Soliman EZ, Thomas A, Papademetriou V. Impact of in- .. 119. Alberts MJ, Bhatt DL, Mas J-L, Ohman EM, Hirsch AT, Rother J, Salette G, Goto tensive glycemic control on the incidence of atrial fibrillation and associated .. S, Smith SC, Liau C-S, Wilson PWF, Steg PG; for the REduction of cardiovascular outcomes in patients with type 2 diabetes mellitus (from the .. Atherothrombosis for Continued Health (REACH) Registry Investigators. .. Action to Control Cardiovascular Risk in Diabetes Study). Am J Cardiol 2014; .. Three-year follow-up and event rates in the international REduction of 114:1217–1222. .. Atherothrombosis for Continued Health Registry. Eur Heart J 2009;30: 107. Chang SH, Wu LS, Chiou MJ, Liu JR, Yu KH, Kuo CF, Wen MS, Chen WJ, Yeh .. 2318–2326. YH, See LC. Association of metformin with lower atrial fibrillation risk among .. 120. Verma S, Bhatt DL, Bain SC, Buse JB, Mann JFE, Marso SP, Nauck MA, Poulter patients with type 2 diabetes mellitus: a population-based dynamic cohort and .. NR, Pratley RE, Zinman B, Michelsen MM, Monk Fries T, Rasmussen S, Leiter in vitro studies. Cardiovasc Diabetol 2014;13:123. .. LA, Leader PC, On B, Of The LTI; LEADER Publication Committee on behalf of 108. Zhang Z, Zhang X, Korantzopoulos P, Letsas KP, Tse G, Gong M, Meng L, Li G, .. the LEADER Trial Investigators. Effect of liraglutide on cardiovascular events in .. Liu T. Thiazolidinedione use and atrial fibrillation in diabetic patients: a meta- .. patients with type 2 diabetes mellitus and polyvascular disease: results of the analysis. BMC Cardiovasc Disord 2017;17:96. .. LEADER trial. Circulation 2018;137:2179–2183. 109. Zelniker TA, Bonaca MP, Furtado RHM, Mosenzon O, Kuder JF, Murphy SA, .. 121. Fowkes FG, Price JF, Stewart MC, Butcher I, Leng GC, Pell AC, Sandercock PA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Budaj A, Kiss RG, Padilla F, .. Fox KA, Lowe GD, Murray GD; Aspirin for Asymptomatic Atherosclerosis Gause-Nilsson I, Langkilde AM, Raz I, Sabatine MS, Wiviott SD. Effect of dapa- .. Trialists. Aspirin for prevention of cardiovascular events in a general population gliflozin on atrial fibrillation in patients with type 2 diabetes mellitus: insights .. screened for a low ankle brachial index: a randomized controlled trial. JAMA from the DECLARE-TIMI 58 trial. Circulation 2020;141:1227–1234. .. 2010;303:841–848. .. 110. Chan YH, Lee HF, Li PR, Liu JR, Chao TF, Wu LS, Chang SH, Yeh YH, Kuo CT, .. 122. Hiatt WR, Fowkes FG, Heizer G, Berger JS, Baumgartner I, Held P, Katona BG, See LC, Lip GYH. Effectiveness, safety, and major adverse limb events in atrial .. Mahaffey KW, Norgren L, Jones WS, Blomster J, Millegard M, Reist C, Patel fibrillation patients with concomitant diabetes mellitus treated with non-vitamin .. MR; EUCLID Trial Steering Committee and Investigators. Ticagrelor versus clo- K antagonist oral anticoagulants. Cardiovasc Diabetol 2020;19:63. .. pidogrel in symptomatic peripheral artery disease. N Engl J Med 2017;376: 111. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz .. 32–40. MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM. .. 123. Cacoub PP, Bhatt DL, Steg PG, Topol EJ, Creager MA; CHARISMA Comparison of the efficacy and safety of new oral anticoagulants with warfarin .. Investigators. Patients with peripheral arterial disease in the CHARISMA trial. .. in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet .. Eur Heart J 2008;30:192–201. 2014;383:955–962. .. 124. Bonaca MP, Scirica BM, Creager MA, Olin J, Bounameaux H, Dellborg M, Lamp 112. Reddy VY, Doshi SK, Kar S, Gibson DN, Price MJ, Huber K, Horton RP, .. JM, Murphy SA, Braunwald E, Morrow DA. Vorapaxar in patients with periph- Buchbinder M, Neuzil P, Gordon NT, Holmes DR Jr; PREVAIL and PROTECT .. eral artery disease: results from TRA2 P-TIMI 50. Circulation 2013;127: AF Investigators. 5-Year outcomes after left atrial appendage closure: from the .. 1522–1529. PREVAIL and PROTECT AF trials. J Am Coll Cardiol 2017;70:2964–2975. .. 125. Katsanos K, Spiliopoulos S, Saha P, Diamantopoulos A, Karunanithy N, Krokidis 113. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, .. M, Modarai B, Karnabatidis D. Comparative efficacy and safety of different anti- Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, .. platelet agents for prevention of major cardiovascular events and leg amputa- .. Popescu BA, Schotten U, Van Putte B, Vardas P; ESC Scientific Document .. tions in patients with peripheral arterial disease: a systematic review and Group. 2016 ESC Guidelines for the management of atrial fibrillation developed .. network meta-analysis. PLoS One 2015;10:e0135692. in collaboration with EACTS. Eur Heart J 2016;37:2893–2962. .. 126. Anand SS, Bosch J, Eikelboom JW, Connolly SJ, Diaz R, Widimsky P, Aboyans V, 114. Angiolillo DJ, Goodman SG, Bhatt DL, Eikelboom JW, Price MJ, Moliterno DJ, .. Alings M, Kakkar AK, Keltai K, Maggioni AP, Lewis BS, Störk S, Zhu J, Lopez- Cannon CP, Tanguay JF, Granger CB, Mauri L, Holmes DR, Gibson CM, Faxon .. Jaramillo P, O’Donnell M, Commerford PJ, Vinereanu D, Pogosova N, Ryden L, DP. Antithrombotic therapy in patients with atrial fibrillation treated with oral .. Fox KAA, Bhatt DL, Misselwitz F, Varigos JD, Vanassche T, Avezum AA, Chen anticoagulation undergoing percutaneous coronary intervention: a North .. E, Branch K, Leong DP, Bangdiwala SI, Hart RG, Yusuf S; COMPASS .. American Perspective—2018 update. Circulation 2018;138:527–536. .. Investigators. Rivaroxaban with or without aspirin in patients with stable periph- 115. Capodanno D, Huber K, Mehran R, Lip GYH, Faxon DP, Granger CB, Vranckx .. eral or carotid artery disease: an international, randomised, double-blind, pla- P, Lopes RD, Montalescot G, Cannon CP, Ten Berg J, Gersh BJ, Bhatt DL, . cebo-controlled trial. Lancet 2018;391:219–229. 2258 R.A. Ajjan et al. 127. Belch JJ, Dormandy J; CASPAR Writing Committee, Biasi GM, Biasi BM, Cairols .. Antiplatelet Trialists’ Collaborative Group. Antiplatelet therapy after noncar- .. M, Diehm C, Eikelboom B, Golledge J, Jawien A, Lepäntalo M, Norgren L, Hiatt .. dioembolic stroke. Stroke 2019;50:1812–1818. WR, Becquemin JP, Bergqvist D, Clement D, Baumgartner I, Minar E, .. 145. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys Stonebridge P, Vermassen F, Matyas L, Leizorovicz A. Results of the random- .. D, Matias-Guiu J, Rupprecht HJ; MATCH Investigators. Aspirin and clopidogrel ized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery .. compared with clopidogrel alone after recent ischaemic stroke or transient is- for peripheral arterial disease (CASPAR) trial. J Vasc Surg 2010;52:825–833. .. chaemic attack in high-risk patients (MATCH): randomised, double-blind, pla- 128. Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass .. cebo-controlled trial. Lancet 2004;364:331–337. surgery (The Dutch Bypass Oral Anticoagulants or Aspirin Study): a rando- .. 146. January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC Jr, Ellinor .. mised trial. Lancet 2000;355:346–351. .. PT, Ezekowitz MD, Field ME, Furie KL, Heidenreich PA, Murray KT, Shea JB, 129. Sarac TP, Huber TS, Back MR, Ozaki CK, Carlton LM, Flynn TC, Seeger JM. .. Tracy CM, Yancy CW. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ Warfarin improves the outcome of infrainguinal vein bypass grafting at high risk .. ACC/HRS Guideline for the management of patients with atrial fibrillation: a re- for failure. J Vasc Surg 1998;28:446–457. .. port of the American College of Cardiology/American Heart Association Task 130. Bonaca MP, Bauersachs RM, Anand SS, Debus ES, Nehler MR, Patel MR, Fanelli .. Force on Clinical Practice Guidelines and the Heart Rhythm Society in F, Capell WH, Diao L, Jaeger N, Hess CN, Pap AF, Kittelson JM, Gudz I, Matyas .. Collaboration With the Society of Thoracic Surgeons. Circulation 2019;140: L, Krievins DK, Diaz R, Brodmann M, Muehlhofer E, Haskell LP, Berkowitz SD, .. e125–e151. .. Hiatt WR. Rivaroxaban in peripheral artery disease after revascularization. N .. 147. Oldgren J, Healey JS, Ezekowitz M, Commerford P, Avezum A, Pais P, Zhu J, Engl J Med 2020;382:1994–2004. .. Jansky P, Sigamani A, Morillo CA, Liu L, Damasceno A, Grinvalds A, Nakamya J, 131. Capodanno D, Alberts M, Angiolillo DJ. Antithrombotic therapy for secondary .. Reilly PA, Keltai K, Van Gelder IC, Yusufali AH, Watanabe E, Wallentin L, prevention of atherothrombotic events in cerebrovascular disease. Nat Rev .. Connolly SJ, Yusuf S; RE-LY Atrial Fibrillation Registry Investigators. Variations Cardiol 2016;13:609–622. .. in cause and management of atrial fibrillation in a prospective registry of 15,400 132. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker .. emergency department patients in 46 countries: the RE-LY Atrial Fibrillation K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie- .. Registry. Circulation 2014;129:1568–1576. .. Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, .. 148. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Tirschwell DL. Guidelines for the early management of patients with acute is- .. Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, chemic stroke: 2019 update to the 2018 Guidelines for the early management .. Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering of acute ischemic stroke: A Guideline for healthcare professionals from the .. Committee and Investigators. Dabigatran versus warfarin in patients with atrial American Heart Association/American Stroke Association. Stroke 2019;50: .. fibrillation. N Engl J Med 2009;361:1139–1151. e344–e418. .. 149. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al- 133. Johnston SC, Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, Held .. Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz .. P, Jonasson J, Minematsu K, Molina CA, Wang Y, Wong KS; SOCRATES .. JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo Steering Committee and Investigators. Ticagrelor versus aspirin in acute stroke .. AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, or transient ischemic attack. N Engl J Med 2016;375:35–43. .. Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE 134. Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, .. Committees and Investigators. Apixaban versus warfarin in patients with atrial Cui L, Jia J, Dong Q, Xu A, Zeng J, Li Y, Wang Z, Xia H, Johnston SC; .. fibrillation. N Engl J Med 2011;365:981–992. CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or tran- .. 150. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, sient ischemic attack. N Engl J Med 2013;369:11–19. .. Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz 135. Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, .. SD, Fox KAA, Califf RM; the ROCKET AF Steering Committee. Rivaroxaban .. Lindblad AS, Palesch YY; Clinical Research Collaboration, Neurological .. versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–891. Emergencies Treatment Trials Network, and the POINT Investigators. .. 151. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med .. Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, 2018;379:215–225. .. Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; 136. Johnston SC, Amarenco P, Denison H, Evans SR, Himmelmann A, James S, .. ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with Knutsson M, Ladenvall P, Molina CA, Wang Y; THALES Investigators. Ticagrelor .. atrial fibrillation. N Engl J Med 2013;369:2093–2104. and aspirin or aspirin alone in acute ischemic stroke or TIA. N Engl J Med 2020; .. 152. Brambatti M, Darius H, Oldgren J, Clemens A, Noack HH, Brueckmann M, .. 383:207–217. .. Yusuf S, Wallentin L, Ezekowitz MD, Connolly SJ, Healey JS. Comparison of 137. Hankey GJ. Antithrombotic therapy for stroke prevention. Circulation 2019;139: .. dabigatran versus warfarin in diabetic patients with atrial fibrillation: results 1131–1133. .. from the RE-LY trial. Int J Cardiol 2015;196:127–131. 138. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of rando- .. 153. Ezekowitz JA, Lewis BS, Lopes RD, Wojdyla DM, McMurray JJ, Hanna M, Atar mised trials of antiplatelet therapy for prevention of death, myocardial infarc- .. D, Cecilia Bahit M, Keltai M, Lopez-Sendon JL, Pais P, Ruzyllo W, Wallentin L, tion, and stroke in high risk patients. BMJ 2002;324:71–86. .. Granger CB, Alexander JH. Clinical outcomes of patients with diabetes and 139. Rothwell PM, Algra A, Chen Z, Diener HC, Norrving B, Mehta Z. Effects of as- .. atrial fibrillation treated with apixaban: results from the ARISTOTLE trial. Eur .. pirin on risk and severity of early recurrent stroke after transient ischaemic at- .. Heart J Cardiovasc Pharmacother 2015;1:86–94. tack and ischaemic stroke: time-course analysis of randomised trials. Lancet .. 154. Bansilal S, Bloomgarden Z, Halperin JL, Hellkamp AS, Lokhnygina Y, Patel MR, 2016;388:365–375. .. Becker RC, Breithardt G, Hacke W, Hankey GJ, Nessel CC, Singer DE, 140. Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A; ESPRIT Study Group. .. Berkowitz SD, Piccini JP, Mahaffey KW, Fox KA; ROCKET AF Steering Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of .. Committee and Investigators. Efficacy and safety of rivaroxaban in patients with arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367: .. diabetes and nonvalvular atrial fibrillation: the Rivaroxaban Once-daily, Oral, 1665–1673. .. Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for .. 141. Sacco RL, Diener HC, Yusuf S, Cotton D, Ounpuu S, Lawton WA, Palesch Y, .. Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Martin RH, Albers GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, .. Trial). Am Heart J 2015;170:675–682. Dahlof B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, .. 155. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, .. Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Toni D, Vandermaelen C, Voigt T, Weber M, Yoon BW; PRoFESS Study .. Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Group. Aspirin and extended-release dipyridamole versus clopidogrel for re- .. Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans current stroke. N Engl J Med 2008;359:1238–1251. .. AL, Munawar M, O’Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S; 142. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, .. AVERROES Steering Committee and Investigators. Apixaban in patients with .. Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, .. atrial fibrillation. N Engl J Med 2011;364:806–817. Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg .. 156. Paciaroni M, Agnelli G, Falocci N, Caso V, Becattini C, Marcheselli S, Rueckert PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol .. C, Pezzini A, Poli L, Padovani A, Csiba L, Szabo L, Sohn SI, Tassinari T, Abdul- EJ; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for .. Rahim AH, Michel P, Cordier M, Vanacker P, Remillard S, Alberti A, Venti M, the prevention of atherothrombotic events. N Engl J Med 2006;354:1706–1717. .. Scoditti U, Denti L, Orlandi G, Chiti A, Gialdini G, Bovi P, Carletti M, Rigatelli 143. Benavente OR, Hart RG, McClure LA, Szychowski JM, Coffey CS, Pearce LA. .. A, Putaala J, Tatlisumak T, Masotti L, Lorenzini G, Tassi R, Guideri F, Martini G, Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N .. Tsivgoulis G, Vadikolias K, Liantinioti C, Corea F, Del Sette M, Ageno W, De .. Engl J Med 2012;367:817–825. .. Lodovici ML, Bono G, Baldi A, D’Anna S, Sacco S, Carolei A, Tiseo C, 144. Greving JP, Diener HC, Reitsma JB, Bath PM, Csiba L, Hacke W, Kappelle LJ, .. Acciarresi M, D’Amore C, Imberti D, Zabzuni D, Doronin B, Volodina V, Koudstaal PJ, Leys D, Mas JL, Sacco RL, Algra A; for the Cerebrovascular . Consoli D, Galati F, Pieroni A, Toni D, Monaco S, Baronello MM, Barlinn K, Antithrombotic therapy in diabetes 2259 Pallesen LP, Kepplinger J, Bodechtel U, Gerber J, Deleu D, Melikyan G, Ibrahim .. M, D’Amore C, Giulia Mosconi M, Anna Cimini L, Fusaro J, Bovi P, Carletti M, F, Akhtar N, Mosconi MG, Bubba V, Silvestri I, Lees KR. Early recurrence and .. Rigatelli A, Cappellari M, Putaala J, Tomppo L, Tatlisumak T, Marcheselli S, cerebral bleeding in patients with acute ischemic stroke and atrial fibrillation: ef- .. Pezzini A, Poli L, Padovani A, Masotti L, Vannucchi V, Sohn S-I, Lorenzini G, .. fect of anticoagulation and its timing: the RAF study. Stroke 2015;46:2175–2182. .. Tassi R, Guideri F, Acampa M, Martini G, Ntaios G, Athanasakis G, Makaritsis K, 157. Paciaroni M, Agnelli G, Falocci N, Tsivgoulis G, Vadikolias K, Liantinioti C, .. Karagkiozi E, Vadikolias K, Liantinioti C, Chondrogianni M, Mumoli N, Consoli Chondrogianni M, Bovi P, Carletti M, Cappellari M, Zedde M, Ntaios G, .. D, Galati F, Sacco S, Carolei A, Tiseo C, Corea F, Ageno W, Bellesini M, Karagkiozi E, Athanasakis G, Makaritsis K, Silvestrelli G, Lanari A, Ciccone A, .. Silvestrelli G, Ciccone A, Lanari A, Scoditti U, Denti L, Mancuso M, Maccarrone Putaala J, Tomppo L, Tatlisumak T, Abdul-Rahim AH, Lees KR, Alberti A, Venti .. M, Ulivi L, Orlandi G, Giannini N, Gialdini G, Tassinari T, De Lodovici ML, Bono M, Acciarresi M, D’Amore C, Becattini C, Mosconi MG, Cimini LA, Soloperto .. G, Rueckert C, Baldi A, D’Anna S, Toni D, Letteri F, Giuntini M, Maria Lotti E, R, Masotti L, Vannucchi V, Lorenzini G, Tassi R, Guideri F, Acampa M, Martini .. Flomin Y, Pieroni A, Kargiotis O, Karapanayiotides T, Monaco S, Maimone .. G, Sohn SI, Marcheselli S, Mumoli N, De Lodovici ML, Bono G, Furie KL, Tadi .. Baronello M, Csiba L, Szabó L, Chiti A, Giorli E, Del Sette M, Imberti D, P, Yaghi S, Toni D, Letteri F, Tassinari T, Kargiotis O, Lotti EM, Flomin Y, .. Zabzuni D, Doronin B, Volodina V, Michel P, Vanacker P, Barlinn K, Pallesen L- Mancuso M, Maccarrone M, Giannini N, Bandini F, Pezzini A, Poli L, Padovani A, .. P, Barlinn J, Deleu D, Melikyan G, Ibrahim F, Akhtar N, Gourbali V, Paciaroni M. Scoditti U, Denti L, Consoli D, Galati F, Sacco S, Carolei A, Tiseo C, Gourbali .. Anticoagulation after stroke in patients with atrial fibrillation. Stroke 2019;50: V, Orlandi G, Giuntini M, Chiti A, Giorli E, Gialdini G, Corea F, Ageno W, .. 2093–2100. Bellesini M, Colombo G, Monaco S, Maimone BM, Karapanayiotides T, Caso V. .. 160. Rocca B, Fox KAA, Ajjan RA, Andreotti F, Baigent C, Collet JP, Grove EL, Early recurrence and major bleeding in patients with acute ischemic stroke and .. Halvorsen S, Huber K, Morais J, Patrono C, Rubboli A, Seljeflot I, Sibbing D, .. atrial fibrillation treated with non-vitamin-K oral anticoagulants (RAF-NOACs) .. Siegbahn A, Ten Berg J, Vilahur G, Verheugt FWA, Wallentin L, Weiss TW, study. J Am Heart Assoc 2017;6:e007034. .. Wojta J, Storey RF. Antithrombotic therapy and body mass: an expert position 158. Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L, Haeusler .. paper of the ESC Working Group on Thrombosis. Eur Heart J 2018;39: KG, Oldgren J, Reinecke H, Roldan-Schilling V, Rowell N, Sinnaeve P, Collins R, ... 1672–1686f. Camm AJ, Heidbüchel H; ESC Scientific Document Group. The 2018 European .. 161. Bhatt DL, Eikelboom JW, Connolly SJ, Steg PG, Anand SS, Verma S, Branch Heart Rhythm Association Practical Guide on the use of non-vitamin K antag- .. KRH, Probstfield J, Bosch J, Shestakovska O, Szarek M, Maggioni AP, Widimsky onist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39: .. P, Avezum A, Diaz R, Lewis BS, Berkowitz SD, Fox KAA, Ryden L, Yusuf S; 1330–1393. .. COMPASS Steering Committee and Investigators. Role of combination antipla- 159. Altavilla R, Caso V, Bandini F, Agnelli G, Tsivgoulis G, Yaghi S, Furie KL, Tadi P, .. telet and anticoagulation therapy in diabetes mellitus and cardiovascular disease: Becattini C, Zedde M, Abdul-Rahim AH, Lees KR, Alberti A, Venti M, Acciarresi .. insights from the COMPASS trial. Circulation 2020;141:1841–1854.